Glycogen synthase kinase 3β inhibitor, composition and process for the preparation thereof

ABSTRACT

Novel compounds having hydroxybenzoimidazole carboxylic amide are useful for inhibiting glycogen synthase kinase 3β(GSK-3β).

FIELD OF THE INVENTION

The present invention relates to a compound for inhibiting glycogen synthase kinase 3beta (GSK-3β) activity, a pharmaceutical composition containing the compound as an active ingredient and a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK-3), the well-known target protein for the treatment of diabetes and dementia, is a serine/threonine protein kinase which inhibits the activity of glycogen synthase (GS) by way of phosphorylation.

In the fatty tissue of mice suffering from fatty diabetes, the GSK-3β activity has been observed to be 2 fold higher than that of a normal mouse (H. Eldar-Finkelman, Diabetes, 48:1662–1666 (1999)) and patients during the second type diabetes are characterized by a high expression level of GSK-3β than normal (S. E. Nikoulina et al., Diabetes, 49: 263–171 (2000)). Also, the GSK-3β activity in the brain of a dementia patient is high (Yamaguchi H. et al., Acta. Neuropathol., 92: 232–241 (1996)), and transgenic mice programmed to express GSK-3β in the brain have abnormal neurons caused by hyperphosphorylating tau of the neurofibrillary tangle which plays an important role in the dementia attack (Lucas J. J. et al., EMBO J. 20: 27–39 (2001)).

GSK-3β is further related to bipolar disorder which can be treated by lithium and valproic acid, well-known GSK-3β inhibitors (Elahi S. et al., J. Infect. Dis. 176: 217–226 (1997)).

Thus, there has existed a need to develop an effective inhibitor of GSK-3β for treating or preventing GSK-β-dependent diseases.

The present inventors have endeavored to develop an effective inhibitor of GSK-3β; and have unexpectedly found that a compound containing a hydroxybenzoimidazole carboxylic amide moiety can inhibit the activity of GSK-3β, and therefore, can be used for treating or preventing GSK-β-dependent diseases such as fatness, diabetes and dementia.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a GSK-3β inhibitor having high inhibitory activity against GSK-3β.

It is another object of the present invention to provide a process for preparing said inhibitor.

It is further object of the present invention to provide a pharmaceutical composition for inhibiting GSK-3β.

In accordance with one aspect of the present invention, there is provided a compound of formula (I), a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof:

wherein:

n is 0, 1, 2 or 3;

R¹, R² and R³ are each independently hydrogen, hydroxy, halogen or morpholin-1-yl-ethylamino;

R⁴ and R⁵ are each independently hydrogen;

linear or cyclic C₁–C₆ alkyl optionally having one or more substituents, the carbon of the alkyl being optionally replaced with nitrogen, sulfur or oxygen, wherein the substituent is: hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido; alkanesulfonyl; amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amido, dioxoisoindole and sulfonylamino; an aromatic group having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido, the aromatic ring having nitrogen, sulfur or oxygen; or cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido;

an aromatic group optionally having one or more substituents, the aromatic ring having optional nitrogen, sulfur or oxygen, wherein the substituent is; hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; or linear or cyclic C₁–C₆ alkyl optionally having one or more substituents, the alkyl having an optional nitrogen, sulfur or oxygen linkage and the substituent of the alkyl being: hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy; halogen; alkyloxy; allyl; amino; alkylamino; carboxyl; nitro; amido; dioxoisoindole; and a sulfonylamino having an aromatic group substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, sulfonylamido, alkanesulfonyl or amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, sulfonylamide, alkanesulfonyl and amido, the aromatic ring containing nitrogen, sulfur or oxygen; or a cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido; or

form, together with the —N—(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycle optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, the heterocycle containing optional nitrogen or oxygen.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula (I) of the present invention, the preferred are:

those wherein n, R¹, R² and R³ have the same meanings as defined previously;

R⁴ and R⁵ are each independently hydrogen;

C₁–C₄ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, and an aromatic group, the aromatic group optionally having one or more substituents selected from the group consisting of OH, C₁–C₄ alkyloxy, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino and dioxoisoindole; cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂; C₁–C₄ alkyl carrying a morpholine or oxopyrrolidine group which is optionally substituted with OH, NH₂, NO₂ or —O—; C₁–C₄ alkyl or C₁–C₄ aminoalkyl carrying a pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, isothiazole, thiazolidine, tiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,2,5-thiadiazole, 1,2,3-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine or triazine group which is optionally having one or more substituents selected from the group consisting of Cl, OH, NH₂, NO₂, C₁–C₄ and phenyl;

cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂;

an aromatic group optionally having one or more substituents selected from the group consisting of OH; NH₂; hydroxyalkyl; aminoalkyl; NO₂; and a C₁–C₄ alkyl group optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunensulfonylamino, dioxoisoindole and thiophensulfonylamino; or

form, together with the —N—(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycle optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂, the heterocycle containing 1 to 3 nitrogen, sulfur or oxygen atom.

In the present invention, the compounds of formula (I) as the below are most preferred: those wherein n, R¹, R² and R³ have the same meanings as defined previously; R⁴ and R⁵ are each independently hydrogen;

C₁–C₄ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, morpholine, nitropyridineamino, pyridine, oxopyrrolidine, imidazole optionally having a Cl, CH₃ or phenyl substituent; and phenyl optionally having one or more substituents selected from the group consisting of OH, NH₂, methoxy, NO₂, methanesulfonylamino, ethanesulfonylamino, toluenesulfonylamino and dioxoisoindole;

cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂;

phenyl optionally having one or more substituents selected from the group consisting of OH; NH₂; NO₂; and C₁–C₄ alkyl optionally having a OH, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino, dioxoisoindole or thiophensulfonylamino substituent; or

form, together with —N—(CH₂)_(n)— moiety to which they are attached, a piperidine ring optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂.

Important compounds of the present invention are listed in Table 1 below.

TABLE 1 Com No. n R¹ R² R³ R⁴ R⁵  1 0 H H H H H  2 0 H H H H Phenyl  3 0 H H H H 4-hydroxyphenyl  4 0 H H H H 4-aminophenyl  5 0 H H H H 4-hydroxycyclohexyl  6 0 H H H H 4-(hydroxymethyl)phenyl  7 0 H H H H 4-(hydroxyethyl)phenyl  8 0 H H H H 4-(aminoethyl)phenyl  9 0 H H H H 4-(p-toluenesulfonamidylethyl)phenyl  10 0 H H H H 4-(methanesulfonamidylethyl)phenyl  11 0 H H H H 4-(phthalinidylethyl)phenyl  12 0 H H H H 4-(2-thiophenylsulfonamidylethyl)phenyl  13 0 H H H H 4-(ethansulfonamidylethyl)phenyl  14 0 H H Cl H phenyl  15 0 H H Cl H 4-hydroxycyclohexyl  16 0 H H Cl H 4-(p-toluenesulfonamidylethyl)phenyl  17 0 H H Cl H 4-(methanesulfonamidylethyl)phenyl  18 0 H H Cl H 4-(phthalinidylethyl)phenyl  19 0 H H Cl H 4-(2-thiophenylsulfonamidylethyl)phenyl  20 0 H H Cl H 4-(ethansulfonamidylethyl)phenyl  21 0 Cl H Cl H H  22 0 Cl H Cl H Phenyl  23 0 Cl H Cl H 4-hydroxycyclohexyl  24 0 Cl H Cl H 4-(aminoethyl)phenyl  25 0 Cl H Cl H 4-aminophenyl  26 0 Cl H Cl H 4-(hydroxymethyl)phenyl  27 0 Cl H Cl H 4-(hydroxyethyl)phenyl  28 0 Cl H Cl H 4-(p-toluenesulfonamidylethyl)phenyl  29 0 Cl H Cl H 4-(methanesulfonamidylethyl)phenyl  30 0 Cl H Cl H 4-(phthalinidylethyl)phenyl  31 0 Cl H Cl H 4-(2-thiophenylsulfonamidylethyl)phenyl  32 0 Cl H Cl H 4-(ethansulfonamidylethyl)phenyl  33 0 H H F H 4-(methanesulfonarnidylethyl)phenyl  34 0 H H F H 4-(p-toluenesulfonamidylethyl)phenyl  35 0 H H F H 4-(ethansulfonamidylethyl)phenyl  36 0 H H F H 4-morpholinophenyl  37 0 F H F H 4-(methanesulfonamidylethyl)phenyl  38 0 F H F H 4-(p-toluenesulfonamidylethyl)phenyl  39 0 F H F H 4-(ethanesulfonamidylethyl)phenyl  40 0 Cl H F H 4-(p-toluenesulfonamidylethyl)phenyl  41 0 Cl H F H 4-(methanesulfonamidylethyl)phenyl  42 0 Cl H F H 4-(ethanesulfonamidylethyl)phenyl  43 0 H Cl F H 4-(p-toluenesulfonamidylethyl)phenyl  44 0 H Cl F H 4-(ethanesulfonamidylethyl)phenyl  45 0 H Cl F H 4-(methanesulfonamidylethyl)phenyl  46 0 H H H R⁴, R⁵ = piperidinyl  47 0 H H Cl R⁴, R⁵ = piperidinyl  48 0 Cl H Cl R⁴, R⁵ = piperidinyl  49 1 H H H H 4-nitrophenyl  50 1 H H H H 4-aminophenyl  51 1 H H H H phenyl  52 1 H H Cl H phenyl  53 1 H H Cl H 4-nitrophenyl  54 1 H H Cl H 4-aminophenyl  55 1 Cl H Cl H phenyl  56 1 Cl H Cl H 4-nitrophenyl  57 2 H H H H phenyl  58 2 H H H H 4-hydroxyphenyl  59 2 H H H H 4-nitrophenyl  60 2 H H H H 4-aminophenyl  61 2 H H H H amino  62 2 H H H H 4-hydroxy-3-methoxyphenyl  63 2 H H H H 3-hydroxy-4-methoxyphenyl  64 2 H H H H 4-(methanesulfonamidyl)phenyl  65 2 H H H H 4-(p-toluenesulfonamidyl)phenyl  66 2 H H H H 4-morpholinyl  67 2 H H H H 4-phthlimidophenyl  68 2 H H H ll 4-(ethanesulfonamidyl)phenyl  69 2 H H H H 4-nitro-2-pyridinylamino  70 2 H H H H 2-pyridyl  71 2 H H Cl H phenyl  72 2 H H Cl H 4-nitrophenyl  73 2 H H Cl H 4-aminophenyl  74 2 H H Cl H 4-hydroxyphenyl  75 2 H H Cl H 4-(methanesulfonamidyl)phenyl  76 2 H H Cl H 4-(p-toluenesulfonamidyu)phenyl  77 2 H H Cl H 3-hydroxy-4-methoxyphenyl  78 2 H H Cl H N-morpholinyl  79 2 H H Cl H 4-phthalimidophenyl  80 2 H H Cl H 4-(ethanesulfonamidyl)phenyl  81 2 H H Cl H 4-nitro-2-pyridinylamino  82 2 H H Cl H 2-pyridyl  83 2 H H Cl H 4-imidazolyl  84 2 H H Cl H 4-hydroxyphenyl  85 2 H H Cl H 4-acetylamino-2-pyridylamino  86 2 H H Cl H 4-(4-methylpiperazin-1-yl- acetylamino)phenyl  87 2 H H Cl H 4-(4-ethylpiperazin-1-yl-acetylamino)- phenyl  88 2 H H Cl H 4-(dimethylaminoacetylamino)phenyl  89 2 H H Cl H 4-(diethylaminoacetylamino)phenyl  90 2 H H Cl H 4-aminophenyl  91 2 H H Cl H 4-amino-2-pyridylamino  92 2 H H Cl H 4-(morpholin-4-yl-acetylamino)phenyl  93 2 H H Cl H 4-(N,N-dimethylamino)phenyl  94 2 H H Cl H 4-(morpholin-4-yl-ethoxy)phenyl  95 2 H H Cl H 4-(4-methylpiperazin-1-yl-ethoxy)phenyl  96 2 H H Cl H 2-hydroxyphenyl  97 2 H H Cl H 2-methoxyphenyl  98 2 H H Cl H 3-bromophenyl  99 2 Cl H Cl H phenyl 100 2 Cl H Cl H 4-nitrophenyl 101 2 Cl H Cl H 4-hydroxy-3-methoxyphenyl 102 2 Cl H Cl H 3-hydroxy-4-methoxyphenyl 103 2 Cl H Cl H amino 104 2 Cl H Cl H 4-hydroxyphenyl 105 2 Cl H Cl H 4-(p-toluenesulfonamidyl)phenyl 106 2 Cl H Cl H 4-(methanesulfonamidyl)phenyl 107 2 Cl H Cl H 4-phthlimidophenyl 108 2 Cl H Cl H 4-morpholinyl 109 2 Cl H Cl H 4-(ethanesuffonamidyl)phenyl 110 2 Cl H Cl H 4-nitro-2-pyridinylamino 111 2 Cl H Cl H 2-pyridyl 112 2 Cl H Cl H 4-(acetylaniino)phenyl 113 2 Cl H Cl H 4-(pentanoylamino)phenyl 114 2 H H F H 4-(methanesulfonamidyl)phenyl 115 2 H H F H 4-(p-toluenesulfonamidyl)phenyl 116 2 H H F H 4-(ethanesulfonamidyl)phenyl 117 2 H H F H 4-(acetylamino)phenyl 118 2 H H F H 4-methylpiperazin-1-yl 119 2 H H F H 4-morpholin-1-yl 120 2 H H F H 4-(pentanoylamino)phenyl 121 2 H H F H 4-hydroxyphenyl 122 2 H H F H 4-nitro-2-pyridinylamino 123 2 H H F H 4-(methanesulfonylamino-2-pyridyl)amino 124 2 H H F H 4-(p-toluenesulfonylamino-2-pyridyl)- amino 125 2 H H F H 4-imidazolyl 126 2 H H F H 4-acetylamino-2-pyridylamino 127 2 H H F H 4-(4-methylpiperazin-1-yl- acetylamino)phenyl 128 2 H H F H 4-(4-ethylpiperazin-1-yl-acetylamino)- phenyl 129 2 H H F H 4-(dimethylaminoacetylamino)phenyl 130 2 H H F H 4-(diethylaminoacetylamino)phenyl 131 2 H H F H 4-aminophenyl 132 2 H H F H 4-morpholmophenyl 133 2 H H F H 4-(3-dimethylaminopyrrolidin-1-yl)phenyl 134 2 H H F H 4-(morpholin-4-yl-acetylamino)phenyl 135 2 H H F H 4-(N,N-dimethylamino)phenyl 136 2 H H F H 4-(morpholin-4-yl-ethoxy)phenyl 137 2 H H F H 2-hydroxyphenyl 138 2 H H F H 2-methoxyphenyl 139 2 H H F H 3-bromophenyl 140 2 F H F H 4-(methanesulfonamidyl)phenyl 141 2 F H F H 4-(p-toluenesulfonamidyl)phenyl 142 2 F H F H 4-(ethanesulfonamidyl)phenyl 143 2 Cl H F H 4-(methanesulfonamidyl)phenyl 144 2 Cl H F H 4-(p-toluenesulfonamidyl)phenyl 145 2 Cl H F H 4-(ethanesulfonamidyl)phenyl 146 2 Cl H F H 4-(acetylamino)phenyl 147 2 Cl H F H 4-morpholin-1-yl 148 2 Cl H F H 4-methylpiperazin-1-yl 149 2 Cl H F H 4-(pentanoylamino)phenyl 150 2 Cl H F H 4-hydroxyphenyl 151 2 Cl H F H 4-nitro-2-pyridinylamino 152 2 Cl H F H 4-(methanesulfonylamino-2-pyridyl)amino 153 2 Cl H F H 4-(p-toluenesulfonylamino-2-pyridyl)- amino 154 2 Cl H F H 4-imidazolyl 155 2 Cl H F H 4-acetylamino-2-pyridylamino 156 2 Cl H F H 4-(4-methylpiperazin-1-yl acetylamino)phenyl 157 2 Cl H F H 4-(4-ethylpiperazin-1-yl-acetylamino) phenyl 158 2 Cl H F H 4-(dimethylaminoacetylamino)phenyl 159 2 Cl H F H 4-(diethylaminoacetylamino)phenyl 160 2 H Cl F H 4-(p-toluenesulfonamidyl)phenyl 161 2 H Cl F H 4-(methanesulfonamidyl)phenyl 162 3 H H H H methyl 163 3 H H H H amino 164 3 H H H H 2-oxopyrrolidin-1-yl 165 3 H H H H 1-imidazolyl 166 3 H H H H 4-N-morpholmyl 167 3 H H H H 2-methylimidazol-1-yl 168 3 H H Cl H methyl 169 3 H H Cl H 2-oxopyrrolidin-1-yl 170 3 H H Cl H 1-imidazolyl 171 3 H H Cl H 4-morpholinyl 172 3 H H Cl H 2-phenylimidazol-1-yl 173 3 H H Cl H 4-methylimidazol-1-yl 174 3 H H Cl H 4,5-dichloroimidazo-1-yl 175 3 H H Cl H 2-methylimidazol-1-yl 176 3 Cl H Cl H methyl 177 3 Cl H Cl H 2-oxopyrrolidin-1-yl 178 3 Cl H Cl H 1-imidazolyl 179 3 Cl H Cl H 4-morpholin-yl 180 3 Cl H Cl H 2-phenylimidazol-1-yl 181 3 Cl H Cl H 4-methylimidazol-1-yl 182 3 Cl H Cl H 4,5-dichloroimidazol-1-yl 183 3 Cl H Cl H 2-methylimidazol-1-yl 184 3 Cl H Cl H 2-isopropylimidazol-1-yl 185 3 H H F H 1-imidazolyl 186 3 H H F H 2-isopropylimidazol-1-yl 187 3 H H F H 4-methylimidazol-1-yl 188 3 H H F H 2-methylimidazol-1-yl 189 3 H H F H 2-ethylimidazol-1-yl 190 3 H H F H 4,5-dichloroimidazol-1-yl 191 3 F H F H 2-isopropylimidazol-1-yl 192 3 F H F H 1-imidazolyl 193 3 F H F H 4-methylimidazol-1-yl 194 3 F H F H 4,5-dichloroimidazol-1-yl 195 3 F H F H 2-methylimidazol-1-yl 196 3 F H F H 2-ethylimidazol-1-yl 197 3 F H F H 4,5-dichioroimidazol-1-yl 198 3 Cl H F H 1-imidazolyl 199 3 Cl H F H 4-methylimidazol-1-yl 200 3 Cl H F H 4,5-dichloroimidazol- 1-yl 201 3 Cl H F H 2-methylimidazol- l-yl 202 3 H Cl F H 4-methylimidazol-1-yl 203 3 H Cl F H 1-imidazolyl 204 3 R¹, R² and R⁴ = H 4,5-dichloroimidazol-1-yl R³ = morpholin- 1-yl-ethylamino

The inventive compound (except for the compound wherein R³ is morpholin-1-yl-ethylamino) of formula (Ia) may be prepared as in Scheme 1.

wherein, p-TSA is p-toluenesulfonic acid, DMF is dimethylformamide, THF is tetrahydrofuran, TFA is trifluoroacetic acid, EDCI is ethyl-dimethylaminopropyl-carbodiimide hyrochloride, DMAP is 4-dimethylaminoprydine, HOBt is N-hydroxybenzotriazole, n, R¹, R², R³, R⁴ and R⁵ have the same meanings as defined previously.

As shown in Scheme I, the compound of formula (Ia) can be prepared by reacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol (e.g., methanol or ethanol) to obtain compound (III); adding anhydrous p-toluenesulfonic acid and benzonitrile to the compound (III) thus obtained, refluxing the mixture at 80 to 200° C., adding NaOCl thereto at room temperature and purifying by silica gel column chromatography to obtain compound (IV); dissolving the compound (IV) thus obtained in an alcohol (e.g., methanol or ethanol), adding an aqueous alkali solution (Na₂CO₃, NaHCO₃, K₂CO₂ or KHCO₃ solution) thereto and refluxing the mixture to obtain compound (V); dissolving the compound (V) thus obtained in an organic solvent, e.g., toluene, adding a Lewis acid (e.g., AlCl₃ or BBr₃) thereto and refluxing the mixture to obtain compound (VI); dissolving the compound (V) thus obtained in an alcohol, adding a strong acid, nitric acid or sulfuric acid, thereto at room temperature and refluxing the mixture to obtain compound (VII); dissolving the compound (VII) thus obtained and (4-bromomethylphenoxy)-methyl polystyrene Wang resin in an organic solvent, e.g., DMF, THF or chloroform, adding a base (CsCO₃, Na₂CO₃, NaHCO₃, K₂CO₃ or KHCO₃) and KI thereto (1:3:3:3) and stirring the mixture at 50 to 60° C. for 1 to 24 hours to obtain compound (VIII); dissolving the compound (VIII) thus obtained in an organic solvent, adding an alcohol solution of an alkali hydroxide (e.g., LiOH, NaOH or KOH) thereto and refluxing the mixture to obtain compound (IX); dissolving the compound (IX) thus obtained in an organic solvent, adding R⁴N(CH₂)_(n)R⁵ and a coupling agent (e.g., EDCI/DMAP/HOBt, DCC or pyBop) thereto and stirring the mixture at room temperature to obtain compound (X); and dissolving the compound (X) thus obtained in CH₂Cl₂, adding trifluoroacetic acid thereto and stirring the mixture at room temperature to obtain compound (Ia).

The inventive compound (wherein R³ is morpholin-1-yl-ethylamino) represented to formula (Ib) may be prepared, as in Scheme II.

As shown in Scheme II, the compound of formula (Ib) can be prepared by reacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol (e.g., methanol or ethanol) to obtain compound (III), adding p-toluenesulfonic acid, benzene and 4-nitrobenzonitrile thereto, refluxing the mixture at 80 to 200° C., adding NaOCl thereto at room temperature and purifying by silica gel column chromatography to obtain compound (XI); dissolving the compound (XI) thus obtained in an organic solvent, adding an aqueous alkali solution (e.g., Na2CO3 solution) thereto, refluxing the mixture and purifying by silica gel column chromatography to obtain compound (XII); dissolving the compound (XII) thus obtained in an alcohol, adding Pd/C thereto and refluxing the mixture to obtain compound (XIII); dissolving the compound (XIII) thus obtained in an organic solvent, adding a base (e.g., CsCO3, Na2CO3, NaHCO3, K2CO3 or KHCO3), 2-chloroethylmorphine and potassium iodide thereto and stirring the mixture at room temperature to obtain compound (XIV); dissolving the compound (XIV) obtained thus in an organic solvent, adding an alkali hydrate, stirring the mixture at room temperature to obtain compound (XV); dissolving the compound (XV) thus obtained in an organic solvent, adding 4,5-dichloro-1-(3-aminoprophyl)imidazole and a coupling agent (e.g., EDCI, DMAP or HOBt), stirring the mixture at room temperature and purifying by silica gel column chromatography to obtain compound (XVI); and dissolving the compound (XVI) thus obtained in MC, adding a Lewis acid thereto, stirring the mixture, concentrating the resulting solution under a reduced pressure and purifying by silica gel column chromatography to obtain compound (Ib).

A salt, hydrate, solvate and isomer of the inventive compound of formula (I) may be prepared by employing any of the known methods. The inventive compound of formula (I), a salt, hydrate, solvate or isomer thereof may used for the treatment of GSK-3β-dependent diseases including fatness, diabetes and dementia, by way of inhibiting GSK-3β activity, the inventive compound having an IC₅₀ value in the range of 1 to 10,000 nM.

Accordingly, the present invention includes a pharmaceutical composition which comprises a therapeutically effective amount of the compound of formula (I), a salt, hydrate, solvate or isomer thereof as an active ingredient and a pharmaceutically acceptable carrier; therefore, the pharmaceutical composition of the present invention exerts superior preventive and treating effects on GSK-β-dependent diseases such as fatness, diabetes and dementia and the like.

A pharmaceutical formulation may be prepared in accordance with any of the conventional procedures. In preparing the formulation, the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier, sachet or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient. Thus, the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.

Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.

The pharmaceutical composition of the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous and intramuscular introduction. In case of human, a typical daily dose of the compound of formula (I) may range from about 0.01 to 100 mg/kg body weight, preferably 0.1 to 50 mg/kg body weight, and can be administered in a single dose or in divided doses. However, it should be understood that the amount of the active ingredient actually administered ought to be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age, sex and body weight of the individual patient, and the severity of the patient's symptom; and, therefore, the above dose should not be intended to limit the scope of the invention in any way.

The following examples are intended to further illustrate the present invention without limiting its scope.

PREPARATION EXAMPLE 1 Preparation of Wang Resin (p-benzyloxybenzyl Alcohol Resin)-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (R¹═H, R²═H and R³═H) (1) Preparation of 3-amino-4-methoxy benzoic acid methyl ester

3-amino-4-methoxy benzoic acid (40 g, 0.239 mol) was dissolved in methanol, H₂SO₄ (38.14 ml, 0.717 mol) was added dropwise thereto and refluxed for 12 hours. The resulting mixture was cooled to room temperature and concentrated under a reduced pressure to remove methanol, neutralized with NaHCO₃, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (39 g, 0.215 mol) in a yield of 90%.

¹H NMR (CDCl₃): δ 7.87–7.78 (2H, m), 7.22 (1H, d), 3.93 (3H, s), 3.82 (3H, s)

MW: 181

(2) Preparation of 4-methoxy-3-[(N-chloro-benzimidoyl)-amino]-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.8 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 and benzonitrile (22.77 g, 220.8 mmol) were added thereto and stirred at 180° C. for 5 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (56 Ml, 37.65 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH/CDCl₃=5:95, Merck, Silicagel 60) to obtain the title compound (31 g, 25.10 mmol) in a yield of 88%;

¹H NMR (CDCl₃): δ 7.78 (1H, d), 7.48(1H, s), 7.37–7.24 (5H, m), 6.95 (1H, d), 3.78 (6H, s)

MW: 318

(3) Preparation of 7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester

4-methoxy-3-[(N-chloro-benzimidoyl)-amino]-benzoic acid methyl ester (8 g, 25.10 mmol) obtained in step 1 was dissolved in 50 ml of 50% methanol and NaHCO₃ (5.32 g, 50.20 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (6 g, 15.94 mmol) in a yield of 86%.

¹H NMR (CDCl₃): δ 10.65 (1H, br), 8.23 (2H, d), 7.49 (3H, m), 6.75 (1H, d), 4.13 (3H, s), 3.99 (3H, s)

MW: 282

(4) Preparation of 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid

7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester (4.5 g, 15.94 mmol) obtained in step 3 was dissolved in 100 ml of toluene, aluminum chloride (9.56 g, 71.73 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (3.5 g, 13.77 mmol) in a yield of 86%.

¹H NMR (DMSO-d₆): δ 8.29 (2H; d), 7.68 (1H, d), 7.56–7.49 (3H, m), 6.67 (1H, d)

MW: 254

(5) Preparation of 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester

7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (2.00 g, 7.46 mmol) obtained in step 4 was dissolved in 30 ml of methanol, H₂SO₄ (2.00 ml, 37.28 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which purified by recrystallization from CHCl₃/MeOH/hexane to obtain the title compound (1.7 g, 5.89 mmol) in a yield of 83%.

¹H NMR (CH₃OH-d₄): δ 7.82 (1H, d), 7.42–7.25 (5H, m), 6.64 (1H, d), 4.92 (3H, s)

MW: 268

(6) Preparation of Wang resin (p-benzyloxybenzyl alcohol resin)-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester

p-nitrophenyl carbonate Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 5, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(7) Preparation of Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester

Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 6 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added thereto and refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 2 Preparation of 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹=H, R²=H and R³=Cl) (1) Preparation of 3-[(4-chloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 4-chlorobenzonitrile (22.78 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding 1M NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The concentrate was dissolved in 500 ml of 50% methanol and 5% NaOCl (197 Ml, 132.46 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chlomatography (eluent—MeOH:CDCl3=5:95, Merck, Silicagel 60) to obtain the title compound (19.43 g, 55.19 mmol) in a yield of 50%.

¹H NMR (CH₃OH-d₄): δ 7.62 (2H, m), 7.22–7.15 (4H, m), 6.59 (1H, s), 4.00–3.80 (6H, d)

MW: 352

(2) Preparation of 2-(4-chloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(4-chloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (5.5 g, 15.63 mmol) obtained in step 1 was dissolved in 40 ml of 50% methanol and Na₂CO₃ (3.53 g, 33.26 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.57 g, 8.13 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.15 (2H, d), 7.95 (1H, d), 7.51 (2H, m), 6.75 (1H, d), 4.06 (3H, s)

MW: 316

(3) Preparation of 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-chloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (1.0 g, 3.16 mmol) obtained in step 2 was dissolved in 10 ml of toluene, aluminum chloride (2.11 g, 15.8 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (745 mg, 2.59 mmol) in a yield of 82%.

¹H NMR (CH₃OH-d₄): δ 8.06 (3H, m), 7.50 (2H, m), 6.97 (1H, d)

MW: 288

(4) Preparation of 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (200 mg, 0.69 mmol) obtained in step 3 was dissolved in 5 ml of methanol, H₂SO₄ (0.18 ml, 3.45 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with 1M NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent—MeOH/CDCl₃=5/95, Merck, Silicagel 60) to obtain the title compound (166 mg, 0.55 mmol) in a yield of 80%.

¹H NMR (CH₃OH-d₄): δ 10.75 (1H, Br), 7.89 (3H, m), 7.46 (2H, d), 6.82 (1H, d), 3.39 (3H, s)

MW: 302

(5) Preparation of Wang Resin-Supported 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol) was dissolved in 5 ml of DMF, and 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang resin-supported 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (1:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 3 Preparation of 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═Cl, R²═H and R³═Cl) (1) Preparation of 3-[(2,4-dichloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (20.99 g, 110.04 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.20 mmol) obtained in step 1 of Preparation Example 1 and 2,4-dichlorobenzonitrile (18.99 g, 110.04 mol) were added thereto and stirred at 180° C. for 6 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (30 ml, 20.64 mmol) was added dropwise thereto. After 5 min, the resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl₃=5:95, Merck, Silicagel 60) to obtain the title compound (18 g, 10.32 mmol) in a yield of 84%.

¹H NMR (CDCl₃): δ 8.23 (1H, br), 7.75 (1H, d), 7.44 (1H, d), 7.36–7.26 (2H, m), 7.03 (1H, s), 6.88 (1H, d), 3.96 (3H, s), 3.76 (3H, s)

MW: 318

(2) Preparation of 2-(2,4-dichloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(2,4-dichloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (4 g, 10.32 mmol) obtained in step 1 was dissolved in 50 ml of 50% methanol and NaHCO₃ (2.19 g, 20.64 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (3.2 g, 5.47 mmol) in a yield of 88%.

¹H NMR (CDCl₃): δ 8.54 (1H, d), 7.94 (1H, d), 7.48 (1H, s), 7.42 (1H, d), 6.76 (1H,d), 4.44 (3H, s), 3.99 (3H, s)

MW: 351

(3) Preparation of 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(2,4-dichloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (1.9 g, 5.47 mmol) obtained in step 2 was dissolved in 100 ml of toluene, aluminum chloride (3.61 g, 27.05 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.63 g, 5.03 mmol) in a yield of 92%.

¹H NMR (DMSO-d₆): δ 8.19 (1H, d), 7.78 (1H, d), 7.62–7.55 (2H, m), 6.82 (1H, d)

MW: 323

(4) Preparation of 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.63 g, 5.03 mmol) obtained in step 3 was dissolved in 30 ml of methanol, and H₂SO₄ (1.08 ml, 20.12 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (1.5 g, 3.62 mmol) in a yield of 86%.

¹H NMR (CDCl₃): δ 11.42 (1H, br), 8.21 (1H, d), 7.89 (1H, d), 7.56 (1H, s), 7.38 (1H, d), 6.82 (1H, d), 3.99 (3H, s)

MW: 337

(5) Preparation of Wang resin-supported 2-(2,4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

p-nitrophenyl carbonate Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 2-(2,4-dichloro-phenyl)-7-hydroxy-2H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol), obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang resin-supported 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 4 Preparation of Wang resin-supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═H, R²═H and R³═F) (1) Preparation of 3-[(4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 4-fluorobenzonitrile (20.00 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent—MeOH:CDCl₃=5:95, Merck, Silicagel 60) to obtain the title compound (22.67 g, 75.06 mmol) in a yield of 68%.

¹H NMR (CDCl₃): δ 7.92–7.75 (4H, m), 7.15–7.02 (3H, m), 3.87–3.81 (6H, d)

MW: 302

(2) Preparation of 2-(4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (10 g, 34.48 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (61 ml, 41.38 mmol) was added dropwise thereto at room temperature. After 5 min, Na₂CO₃ (7.31 g, 68.96 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.66 g, 19.65 mmol) in a yield of 57%.

¹H NMR (CDCl₃): δ 8.18 (2H, t), 7.91 (1H, d), 7.30–7.25 (2H, t), 6.65 (1H, d), 6.85 (1H, d), 4.08 (3H, s), 3.98 (3H, s)

MW: 300

(3) Preparation of 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (3 g, 10.00 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (6.67 g, 30.00 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.96 g, 7.20 mmol) in a yield of 72%.

¹H NMR (MeOH-d₄): δ 8.19–8.15 (2H, t), 8.06 (1H, d), 7.50–7.44 (2H, t), 7.00 (1H, d)

MW: 272

(4) Preparation of 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500 mg, 1.84 mmol) obtained in step 3 was dissolved in methanol, H₂SO₄ (0.49 ml, 9.20 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (397 mg, 1.39 mmol) in a yield of 76%.

¹H NMR (CH₃OH-d₄): δ 8.22–8.18 (2H, t), 7.80 (1H, d), 7.32–7.26 (2H, t), 6.70 (1H, d), 3.97 (3H, s)

MW: 286

(5) Preparation of Wang resin-supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang Resin-Supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 5 Preparation of Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═F, R²═H and R³═F) (1) Preparation of 3-[(2,4-difluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (25.0 g, 137.43 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.25 mmol) obtained in step 1 of Preparation Example 1 and 2,4-difluorobenzonitrile (11.53 g, 82.87 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10.0 g, 31.22 mmol) in a yield of 57%.

¹H NMR (CDCl₃): δ 8.31–8.22 (1H, m), 7.82–7.79 (1H, d), 7.65 (1H, s), 7.02–6.85 (3H, m), 3.88 (6H, s)

MW: 320

(2) Preparation of 2-(2,4-difluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(2,4-difluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (9.5 g, 29.66 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto at room temperature. After 5 min, Na_(2l CO) ₃ (6.29 g, 59.34 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.50 g, 11.0 mmol) in a yield of 37%.

¹H NMR (CDCl₃): δ 10.99 (1H, bs). 8.65–8.57 (1H, m), 0.92 (1H, d), 7.10–6.97 (2H, m), 6.76 (1H, d), 4.13 (3H, s), 4.00 (3H, s)

MW: 318

(3) Preparation of 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(2,4-difluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (2.24 g, 7.04 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (3.75 g, 28.12 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.70 g, 5.86 mmol) in a yield of 83%.

¹H NMR (CH₃OH-d₄): δ 8.13–8.03 (2H, m), 7.47–7.33 (2H, m), 7.04 (1H, d)

MW: 290

(4) Preparation of 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.70 mg, 5.86 mmol) obtained in step 3 was dissolved in methanol, SOCl₂ (8.2 ml, 112 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (1.50 mg, 1.64 mmol) in a yield of 84%.

¹H NMR (DMSO-d₆): δ 12.04 (1H, bs), 0.30–8.04 (1H, m), 7.73 (1H, d), 7.55–7.48 (1H, m), 7.33–7.27 (1H, m), 6.70 (1H, d), 4.01 (3H, s)

MW: 304

(5) Preparation of Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 6 Preparation of Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═Cl, R²═H and R³═F) (1) Preparation of 3-[(2-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 2-chloro-4-fluorobenzonitrile (25.76 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (26.70 g, 79.47 mmol) in a yield of 72%.

¹H NMR (CDCl₃): δ 7.92–7.75 (4H, m), 7.15–7.02 (3H, m), 3.87–3.81 (6H, d)

MW: 336

(2) Preparation of 2-(2-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(2-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (10 g, 29.76 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto at room temperature. After 5 min, Na₂CO₃ (6.31 g, 59.52 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.17 g, 15.48 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.18 (2H, t), 0.91 (1H, d), 7.30–7.25 (2H, t), 6.65 (1H, d), 6.85 (1H, d), 4.08 (3H, s), 3.98 (3H, s)

MW: 334

(3) Preparation of 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(2-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (3 g, 8.98 mmol) obtained in step 2 was dissolved in toluene and aluminum chloride (5.99 g, 44.90 mmol) was added thereto, refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.87 g, 6.11 mmol) in a yield of 68%.

¹H NMR (CH₃OH-d₄): δ 8.19–8.15 (2H, t), 8.06 (1H, d), 7.50–7.44 (2H, t), 7.00 (1H, d)

MW: 306

(4) Preparation of 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500 mg, 1.63 mmol) obtained in step 3 was dissolved in methanol, H₂SO₄ (0.43 ml, 8.15 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (393 mg, 1.23 mmol) in a yield of 67%.

¹H NMR (CH₃OH-d₄): δ 8.22–8.18 (2H, t), 7.80 (1H, d), 7.32–7.26 (2H, t), 6.70 (1H, d), 3.97 (3H, s)

MW: 320

(5) Preparation of Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 7 Preparation of Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═H, R²═Cl and R³═F) (1) Preparation of 3-[(3-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (10 g, 52.57 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (3.88 g, 21.44 mmol) obtained in step 1 of Preparation Example 1 and 3-chloro-4-fluorobenzonitrile (5.0 g, 32.14 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.24 g, 9.62 mmol) in a yield of 45%.

¹H NMR (CDCl₃): δ 7.96–7.95 (1H, m), 7.76–7.73 (2H, m), 7.60 (1H, bs), 7.17–7.11 (1H, m), 6.93(1H, d), 3.85(3H, s), 3.84 (3H, d)

MW: 336

(2) Preparation of 2-(3-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(3-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (3.24 g, 9.62 mmol) was dissolved in 50% methanol and 5% NaOCl (18 ml, 11.90 mmol) was added dropwise thereto at room temperature. After 5 min, Na₂CO₃ (2.04 g, 19.25 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (0.95 g, 2.83 mmol) in a yield of 30%.

¹H NMR (CDCl₃): δ 10.68 (1H, bs), 8.23–8.20 (1H, m), 7.96–7.91 (1H, m), 7.87 (1H, d), 7.27–7.20 (1H, m), 6.73 (1H, d), 4.10 (3H, s), 3.97 (3H, s)

MW: 334

(3) Preparation of 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(3-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (0.95 g, 8.98 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (1.5 g, 11.25 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (0.81 g, 2.64 mmol) in a yield of 80%.

¹H NMR (MeOH-d₄): δ 8.34 (1H, dd), 8.22–8.08 (2H, m), 7.62 (1H, t), 7.03 (1H, d)

MW: 306

(4) Preparation of 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (800 mg, 2.64 mmol) obtained in step 3 was dissolved in methanol, SOCl₂ (1.93 ml, 26.41 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO₃. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (690 mg, 2.15 mmol) in a yield of 81%.

¹H NMR (DMSO-d₆): δ 12.39 (1H, bs), 8.56 (1H, d), 8.30 (1H, bs), 7.72 (1H, d), 7.59 (1H, t), 6.69 (1H, d), 3.90 (3H, s)

MW: 320

(5) Preparation of Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol) was dissolved in DMF, and 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60° C. for 12 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in a yield of 98%.

(6) Preparation of Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.

EXAMPLE 1 Preparation of 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide (R⁴R⁵NH₂═NH₄Cl)

Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (36 mg, 0.03 mmol) obtained in Preparation Example 1 was dissolved in 3 ml of DMF and aluminum chloride (5 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol), DMAP (11 mg, 0.09 mmol) and HOBt (12 mg, 0.09 mmol) were added thereto and the resulting mixture was stirred at room temperature. The resulting solution was filtered, the filtrate was washed with DMF, MeOH and CH₂Cl₂ and dried to obtain Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide.

Then, 30 mg of Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide was dissolved in 0.2 ml of CH₂Cl₂, 0.2 ml of trifluoroacetic acid was added thereto and stirred for 30 min. The resulting solution was filtered, the filtrate was washed with MeOH and CH₂Cl₂ and dried to obtain the title compound in a yield of 90%.

¹H NMR (CH₃OH-d₄): δ 8.15 (2H, d), 7.84 (1H, d), 7.78–7.56 (3H, m), 6.83 (1H, m)

MW: 253

EXAMPLE 2 TO 203

The same procedure as described in Example 1 was repeated using R⁴R⁵NH₂ listed in Table 2 to obtain the compounds 2 to 203, respectively.

TABLE 2 Com Pre No. No. Chemical compound R⁴N(CH₂)_(n)R⁵ n ¹H NMR(CH₃OH-d₄) MW  2 1 7-hydroxy-2-phenyl-1H-benzo- aniline 0 δ 8.10(2H, d), 7.87(1H, d), 7.85–7.60(3H, m), 329 imidazole-4-carboxylic 7.40(2H, d), 07.39–7.28(2H, m), 7.27–7.20(1H, acid-phenylamide m), 6.89(1H, d)  3 1 7-hydroxy-2-phenyl-1H- 4-hydroxyaniline 0 δ 8.28–8.03(3H, m), 7.98–7.82(1H, d), 345 benzoimidazole-4-carboxylic 7.79–7.56(3H, m), 7.48(2H, d), 6.85–6.72(2H, m) acid(4-hydroxy-phenyl)-amide  4 1 7-hydroxy-2-phenyl-1H- 1,4-diaminophenylene 0 δ 8.28–8.14(2H, m), 8.03–7.91(3H, m), 344 benzoimidazole-4-carboxylic 7.71–7.56(3H, m), 7.46–7.34(2H, d), acid(4-amino-phenyl)-amide 6.89–6.76(1H, d)  5 1 7-hydroxy-2-phenyl-1H- 4-hydroxycyclohexylamine 0 δ 8.08(2H, d), 7.82(1H, d), 7.78–7.50(3H, m), 351 benzoimidazole-4-carboxylic 6.88(1H, d), 4.15–3.82(1H, m), 3.70–3.54(1H, acid(4-hydroxy-cyclohexyl)- m), 2.30–1.90(4H, m), 1.85–1.20(4H, m) amide  6 1 7-hydroxy-2-phenyl-1H- 4-(hydroxymethyl)aniline 0 δ 8.20(2H, d), 7.92(2H, d), 7.81–7.70(1H, m), 359 benzoimidazole-4-carboxylic 7.69–7.58(3H, m), 7.50–7.30(1H, m), acid(4-hydroxymethyl-phenyl)- 7.29–7.10(1H, m), 6.89(1H, d), 4.65(2H, s) amide  7 1 7-hydroxy-2-phenyl-1H- 4-(hydroxyethyl)aniline 0 δ 8.14(2H, d), 7.98(1H, d), 7.78–7.60(5H, m), 373 benzoimidazole-4-carboxylic 7.30–7.18(2H, m), 6.88(1H, d), 4.65(1H, t), acid[4-(2-hydroxy-ethyl)- 3.73(1H, t), 3.02(1H, t), 2.81(1H, t) phenyl]-amine  8 1 7-hydroxy-2-phenyl-1H- 4-(aminoethyl)aniline 0 δ 8.27–8.16(2H, m), 7.95(1H, d), 7.78(2H, d), 372 benzoimidazole-4-carboxylic 7.66–7.54(3H, m), 7.44(2H, d), 6.86(1H, d), acid[4-(2-amino-ethyl)-phenyl]- 3.19(2H, t), 2.92(2H, t) amide  9 1 7-hydroxy-2-phenyl-1H- N-[2-(4-amino-phenyl)- 0 δ 8.20–8.02(3H, m), 8.00(2H, d), 7.70–7.68(5H, 526 benzoimidazole-4-carboxylic ethyl]-4-methylbenzene- m), 7.38(2H, d), 7.16(2H, d), 6.94(1H, d), acid{4-[2-(toluene-4-sulfonyl- sulfonamide 3.10(2H, t), 2.73(2H, t), 2.43(3H, s) amino)-ethyl]-phenyl}-amide  10 1 7-hydroxy-2-phenyl-1H- N-[2-(4-amino-phenyl)- 0 δ 8.13(2H, d), 7.98(1H, d), 7.75–7.53(5H, m), 450 benzoimidazole-4-carboxylic ethyl]-4-methane- 7.29(2H,d), 6.91(1H, d), 3.30(2H, t), 2.82(2H, t) acid[4-(2-methanesulfonyl- sulfonamide amino-ethyl)-phenyl]-amide  11 1 7-hydroxy-2-phenyl-1H- 2-[2-(4-aminophenyl)- 0 δ 7.45(2H, d), 6.98–6.84(4H, m), 6.82(2H, d), 502 benzoimidazole-4-carboxylic- ethyl]-isoindole-1,3-dione 6.73–6.54(4H, m), 6.30(2H, d), 5.89(1H, d), acid{4-[2-(1,3-dioxo-1,3- 2.91(2H, t), 2.00(2H, t) dihydro-isoindole-2-yl)-ethyl]- phenyl}-amide  12 1 7-hydroxy-2-phenyl-1H- thiophene-2-sulfonic acid 0 δ 8.15(2H, d), 8.06(1H, d), 7.80–7.55(7H, m), 518 benzoimidazole-4-carboxylic [2-(4-amino-phenyl)- 7.23–7.10(3H, m), 7.05(1H, d), 3.16(2H, t), acid{4-[2-(thiophene-2- ethyl]-amide 2.80(2H, t) sulfonylamino)-ethyl]-phenyl}- amide  13 1 7-hydroxy-2-phenyl-1H- N-[2-(4-amino-phenyl)- 0 δ 8.17(2H, d), 8.03(1H, d), 7.77–7.68(5H, m), 464 benzoimidazole-4-carboxylic ethyl]-ethanesulfonamide 7.27(2H, d), 7.01(1H, d), 3.31(2H, t), 2.99(2H, acid[4-(2-ethanesulfonylamino- q), 2.85(2H, t), 1.23(3H, t) ethyl)-phenyl]-amide  14 2 2-(4-chloro-phenyl)-7-hydroxy- aniline 0 δ 8.18(2H, d), 8.11(1H, d), 7.80(2H, d), 7.67(2H, 363 1H-benzoimidazole-4-carboxylic d), 7.40(2H, t), 7.15(1H, t), 6.89(1H, d) acid phenylamide  15 2 2-(4-chloro-phenyl)-7-hydroxy- 4-hydroxycyclo- 0 δ 8.15(2H, d), 7,84(1H, d), 7.69(2H, d), 6.90(1H, 385 1H-benzoimidazole-4-carboxylic hexylamine d), 3.95(1H, m), 3.58(1H, m), 2.28–1.95(4H, m), acid(4-hydroycyclohexyl)-amide 1.83–1.25(4H, m)  16 2 2-(4-chloro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.18(2H, d), 7.98(1H, d), 7.80–7.60(6H, m), 560 1H-benzoimidazole-4-carboxylic ethyl]-4-methyl- 7.36(2H, d), 7.16(2H, d), 6.94(1H, d), 3.09(2H, acid{4-[2-(toluene-4-sulfonyl- benzenesulfonamide t), 2.74(2H, t), 2.41(3H, s) amino)-ethyl]-phenyl}-amide  17 2 2-(4-chloro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.15(1H, d), 7.94(1H, d), 7.72(2H, d), 7.62(2H, 484 1H-benzoimidazole-4-carboxylic ethyl]-methenesulfonyl- d), 7.28(2H, d), 6.85(1H, d), 3.32(2H, t), acid[4-(2-methanesulfonyl- amide 2.85(3H, s), 2.84(2H, t) amino-ethyl)-phenyl]-amide  18 2 2-(4-chloro-phenyl-7-hydroxy- 2-[2-(4-amino-phenyl)- 0 δ 8.16(2H, d), 8.02(1H, d), 7.86–7.76(4H, m), 536 1H-benzoimidazole-4-carboxylic ethyl]-isoindole-1,3-dione 7.75–7.61(4H, m), 7.22(2H, d), 6.95(1H, m), acid{4-[2-(1,3-dioxo-1,3- 3.90(2H, t), 2.97(2H, t) dihydro-isoindole-2-yl)-ethyl]- phenyl}-amide  19 2 2-(4-chloro-phenyl)-7-hydroxy- thiophene-2-sulfonic 0 δ 8.15(2H, d), 7.97(2H, d), 7.75–7.57(6H, m), 552 1H-benzoimidazole-4-carboxylic acid[2-(4-amino-phenyl)- 7.19(2H, d), 6.92(1H, d), 3.17(2H, t), 2.77(2H, t) acid{4-[2-(thiophene-2-sulfonyl- ethyl]-amide amino-ethyl)-phenyl]-amide  20 2 2-(4-chloro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.17(2H, d), 8.09(2H, d), 7.73(2H, d), 7.63(2H, 498 1H-benzoimidazole-4-carboxylic ethyl]-ethanesulfonylamide d), 7.29(2H, d), 3.31(2H, t), 2.98(2H, q), acid[4-(2-ethanesulfonylamino- 2.85(2H, t), 1.24(3H, t) ethyl)-phenyl]-amide  21 3 2-(2,4-dichloro-phenyl)-7- ammonium chloride 0 δ 7.98–7.70(2H, m), 7.69–7.52(1H, m), 321 hydroxy-1H-benzoimidazole-4- 7.28–7.00(1H, m), 6.95–6.82(1H, m) carboxylic acid phenylamide  22 3 2-(2,4-dichloro-phenyl)-7- aniline 0 δ 8.02(1H, d), 8.01–7.82(1H, m), 7.81–7.65(3H, 397 hydroxy-1H-benzoimidazole-4- m), 7.64–7.45(1H, m), 7.43–7.20(2H, t), carboxylic acid phenylamide 7.42–7.02(1H, t), 6.90(1H, d)  23 3 2-(2,4-dichloro-phenyl)-7- 4-hydroxy-cyclohexyl- 0 δ 8.02–7.68(2H, m), 7.68–7.48(1H, m), 419 hydroxy-1H-benzoimidazole-4- amine 7.20–7.03(1H, m), 6.88(1H, d), 3.93(1H, m), carboxylic acid(4-hydroxy- 3.58(1H, m), 2.25–1.85(4H, m), cyclohexyl)-amide 1.84–1.39(4H, m)  24 3 2-(2,4-dichloro-phenyl)-7- 4-aminophenethylamine 0 δ 7.97(2H, d), 7.85–7.63(3H, m), 7.56(1H, d), 440 hydroxy-1H-benzoimidazole-4- 7.38–7.20(2H, m), 6.82(1H, d), 3.18(2H, t), carboxylic acid[4-(2-amino- 2.96(2H, t) ethyl)-phenyl]-amide  25 3 2-(2,4-Dichloro-phenyl)-7- 1,4-phenylenediamine 0 δ 8.06–7.81(4H, m), 7.80–7.64(1H, s), 7.58(1H, 412 hydroxy-1H-benzoimidazole-4- d), 7,38(2H, d), 6.84(1H, d) carboxylic acid(4-amino- phenyl)-amide  26 3 2-(2,4-Dichloro-phenyl)-7- 4-aminobenzy alcohol 0 δ 8.00(1H, d), 7.98–7.84(1H, m), 7.75(1H, m), 427 hydroxy-1H-benzoimidazole-4- 7.74–7.52(2H, m), 7.50–7.26(1H, m), carboxylic acid(4-hydroxy- 7.25–7.05(2H, m), 7.04–6.80(1H, m) methyl-phenyl)-amide  27 3 2-(2,4-Dichloro-phenyl)-7- 4-aminophenethyl alcohol 0 δ 8.15–7.86(2H, m), 7.85–7.45(3H, m), 7.25(2H, 441 hydroxy-1H-benzoimidazole-4- d), 7.20–6.75(2H, m), 4.58(1H, t), 3.75(1H, t), carboxylic acid[4-(2-hydroxy- 3.05(1H, t), 2.81(1H, t) ethyl)-phenyl]-amide  28 3 2-(2,4-dichloro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 8.20–8.02(3H, m), 8.00(2H, d), 7.70–7.68(3H, 594 hydroxy-1H-benzoimidizaole-4- ethyl]-4-methyl-benzene- m), 7.38(2H, d), 7.16(2H, d), 6.94(1H, d), carboxylic acid{4-[2-(toluene- sulfonamide 3.10(2H, t), 2.73(2H, t), 2.43(3H, s) 4-sulfonylamino)-ethyl]- phenyl}-amide  29 3 2-(2,4-dichloro-phenyl)-7- N-[2(4-amino-phenyl)- 0 δ 8.02(1H, d), 8.01–7.78(1H, m), 7.70(2H, d), 518 hydroxy-1H-benzoimidazole-4- ethyl]-methanesulfonamide 7.67–7.50(1H, m), 7.25(2H, d), 6.90(2H, d), carboxylic acid[4-(2-methane- 3.28(2H, t), 2.84(2H, t), 2.82(3H, s) sulfonylamino-ethyl)-phenyl]- amide  30 3 2-(2,4-dichloro-phenyl)-7- 2-[2-(4-amino-phenyl)- 0 δ 7.10(1H, d), 6.99–6.81(6H, m), 6.80–6.65(3H, 570 hydroxy-1H-benzoimidazole-4- ethyl]-isoindole-1,3-dione m), 6.28(2H, d), 5.92(1H, d), 2.88(2H, t), carboxylic acid{4-[2-(1,3- 1.97(2H, t) dioxo-1,3-dihydro-isoindole-2- yl)-ethyl]-phenyl}-amide  31 3 2-(2,4-dichloro-phenyl)-7- thiophene-2-sulfonic 0 δ 8.08(1H, d), 7.88(2H, m), 7.83(1H, d), 586 hydroxy-1H-benzoimidazole-4- acid[2-(4-amino-phenyl)- 7.75(1H, d), 7.68–7.65(3H, m), 7.63(1H, d), carboxylic acid{4-[2-(thiophene- ethyl]-amide 7.17–7.01(2H, m), 6.97(1H, d), 3.16(2H, t), 2-sulfonylamino)-ethyl]- 2.77(2H, t) phenyl}-amide  32 3 2-(2,4-dichloro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 8.11(1H, d), 7.95–7.82(2H, m), 7.75–7.60(3H, 532 hydrioxy-1H-benzoimidazole-4- ethyl]-ethanesulfonamide m), 7.28(2H, d), 7.01(1H, d), 3.31(2H, t), carboxylic acid[4-(2-ethane- 2.98(2H, q), 2.85(2H, t), 1.24(3H, t) sulfonylamino-ethyl)-phenyl]- amide  33 4 2-(4-fluoro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.23–8.15(2H, m), 7.91(1H, d), 7.69(2H, d), 1H-benzoimidazole-4-carboxylic ethyl]-methanesulfonamide 7.39(2H, t), 7.26(2H, d), 6.83(1H, d), 3.31(2H, t), acid[4-(2-methanesulfonyl- 2.85–2.78(5H, m) amino-ethyl)-phenyl]-amide  34 4 2-(4-fluoro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.25–8.21(2H, m), 7.98–7.93(2H, m), 1H-benzoimidazole-4-carboxylic ethyl]-4-methyl- 7.71–7.64(4H, m), 7.41–7.34(3H, m), 7.14(2H, acid{4-[2-(toluene-4-sulfonyl- benzenesulfonamide d), 6.87(1H, d), 3.08(2H, t), 2.73(2H, t), amino)-ethyl]-amide 2.40(3H, s)  35 4 2-(4-fluoro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.05(2H, t), 7.78(1H, d), 7.30(2H, t), 7.14(2H, 1H-benzoimidazole-4-carboxylic ethyl]-ethanesulfonamide d), 6.77(2H, d), 6.69(1H, d), 3.78(2H, q), acid[4-(2-methanesulfonyl- 3.35(2H, t), 2.90(2H, t), 1.28(3H, t) amino-ethyl)-phenyl]-amide  36 4 2-(4-fluoro-phenyl)-7-hydroxy- 4-morpholin-4-yl- 0 1H-benzoimidazole-4-carboxylic phenylamine acid(4-morpholin-4-yl-phenyl)- amide  37 5 2-(2,4-difluoro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 7.90(1H, d), 7.62(1H, d), 7.31–7.17(4H, m), hydroxy-1H-benzoimidazole-4- ethyl]-methanesulfonamide 6.81(1H, d), 3.22(2H, t), 2.76(5H, m) carboxylic acid[4-(2-methane- sulfonylamino-ethyl)-phenyl]- amide  38 5 2-(2,4-difluoro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 7.99(1H, m), 7.74(1H, d), 7.50(2H, d), hydroxy-1H-benzoimidazole-4- ethyl]-4-methyl-benzene- 7.33–7.26(2H, m), 7.23(4H, m), 6.94(2H, d), carboxylic acid {4-[2-(toluene- sulfonamide 6.81(1H, d), 3.58(2H, t), 2.82(2H, t), 2.23(3H, s) 4-sulfonylamino)-ethyl]- phenyl}amide  39 5 2-(2,4-difluoro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 8.19–8.00(2H, m), 7.70(1H, d), 7.43–7.26(4H, hydroxy-1H-benzoimidazole-4- ethyl]-ethanesulfonamide m), 6.87(1H, d), 3.98(2H, t), 2.97(2H, q), carboxylic acid[4-(2-methane- 2.86(2H, t), 1.25(3H, t) sulfonylamino-ethyl)-phenyl]- amide  40 6 2-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.01–7.93(1H, m), 7.65(3H, t), 7.53–7.44(2H, 7-hydroxy-1H-benzoimidazole- ethyl]-4-methyl-benzene- m), 7.33(4H, m), 7.11(2H, d), 6.80(1H, d), 4-carboxylic acid{4-[2- sulfonamide) 3.09(2H, t), 2.72(2H, t), 2.38(3H, s) (toluene-4-sulfonylamino)- ethyl]-phenyl}amide  41 6 2-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.06(1H, m), 7.97(1H, d), 7.68–7.61(3H, m), 7-hydroxy-1H-benzoimidazole- ethyl]-methanesulfonamide 7.40(1H, m), 7.27(2H, m), 6.97(1H, m), 3.61(2H, 4-carboxylic acid[4-(2- t), 2.84(5H, m) methanesulfonylamino-ethyl)- phenyl]-amide  42 6 2-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.07(1H, m), 7.97(1H, d), 7.68–7.40(3H, 7-hydroxy-1H-benzoimidazole- ethyl]ethanesulfonamide m), 7.28–7.18(3H, m), 6.99(1H, d), 3.61(2H, t), 4-carboxylic acid[4-(2- 2.96(2H, q), 2.84(2H, t), 1.28(3H, t) methanesulfonylamino-ethyl)- phenyl]-amide  43 7 2-(3-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.18(1H, d), 7.90(1H, m), 7.72(1H, d), 7-hydroxy-1H-benzoimidazole- ethyl]-4-methyl-benzene- 7.47(2H, d), 7.39(1H, m), 7.13–7.06(4H, m), 4-carboxylic acid{4-[2- sulfonamide 6.95(2H, d), 6.75(1H, d), 3.63(2H, t), 2.85(2H, t), (toluene-4-sulfonylamino)- 2.23(3H, s) ethyl]-phenyl}amide  44 7 2-(3-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.27(1H, d), 8.10(1H, m), 7.85(1H, d), 7-hydroxy-1H-benzoimidazole- ethyl]-ethanesulfonamide 7.64(2H, d), 7.41(1H, t), 7.22(2H, d), 6.76(1H, 4-carboxylic acid{4-[2- d), 3.26(2H, t), 2.94(2H, q), 2.80(2H, t), methanesulfonylamino)- 1.22(3H, t) ethyl)-phenyl]amide  45 7 2-(3-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.31(1H, d), 8.12(1H, m), 7.91(1H, d), 7-hydroxy-1H-benzoimidazole- ethyl]-methanesulfonamide 7.68(2H, d), 7.47(1H, t), 7.26(2H, d), 6.83(1H, 4-carboxylic acid[4-(2- d), 3.31(2H, t), 2.85(5H, m) methanesulfonylamino-ethyl)- phenyl]-amide  46 1 cyclohexyl-(7-hydroxy-2- piperidine 0 δ 7.31–7.23(5H, m), 7.05(1H, d), 6.64(1H, d), 320 phenyl-1H-benzoimidazole-4- 3.53–3.29(4H, m), 1.82–1.41(6H, m) yl)-methanone  47 2 2-(4-chloro-phenyl)-7-hydroxy- piperidine 0 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 6.92(1H, 355 1H-benzoimidazole-4-carboxylic d), 3.53–3.29(4H, m), 1.82–1.41(6H, m) acid cyclohexyl-amide  48 3 2-(2,4-dichloro-phenyl)-7- piperidine 0 δ 7.31–7.23(3H, m), 7.05(1H, d), 6.64(1H, d), 389 hydroxy-1H-benzoimidazole-4- 3.53–3.29(4H, m), 1.82–1.41(6H, m) yl-piperidine-1-yl-methanone  49 1 7-hydroxy-2-phenyl-1H-benzo- 4-nitrobenzylamine- 1 δ 8.20(2H, d), 8.13(2H, d), 7.82(1H, d), 388 imidazole-4-carboxylic acid(4- hydrochloride) 7.82–7.55(5H, m), 6.87(1H, d), 4.75(2H, s) nitro-benzyl)-amide  50 1 7-hydroxy-2-phenyl-1H-benzo- 4-aminobenzylamine- 1 δ 8.15(2H, d), 7.82(1H, d), 7.72–7.52(5H, m), 358 imidazole-4-carboxylic acid dihydro chloride 7.33(2H, d), 6.87(1H, d), 4.70(2H, s) (4-amino-benzyl)-amide  51 1 7-hydroxy-2-phenyl-1H-benzo- benzylamine 1 δ 8.10(2H, d), 7.87(1H, d), 7.85–7.60(3H, m), 343 imidazole-4-carboxylic acid 7.40(2H, d), 7.39–7.28(2H, m), 7.27–7.20(1H, benzylamide m), 6.89(1H, d), 4.66(2H, s)  52 2 2-(4-chloro-phenyl)-7-hydroxy- benzylamine 1 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 377 1H-benzoimidazole-4-carboxylic 7.42–7.23(5H, m), 6.92(1H, d), 4.68(2H, s) acid benzylamide  53 2 2-(4-chloro-phenyl)-7-hydroxy- 4-nitrobenzylamine- 1 δ 8.20(2H, d), 7.90(2H, d), 7.88(1H, s), 422 1H-benzoimidazole-4-carboxylic hydrochloride 7.69–7.51(4H, m), 6.91(1H, d), 4.76(2H, s) acid(4-nitro-benzyl)-amide  54 2 2-(4-chloro-phenyl)-7-hydroxy- 4-aminobenzylamine- 1 δ 8.20(2H, d), 7.90(2H, d), 7.88(1H, s), 392 1H-benzoimidazole-4-carboxylic hydroxy chloride 7.69–7.51(4H, m), 6.91(1H, d), 4.76(2H, s) acid(4-amino-benzyl)-amide  55 3 2-(2,4-dichloro-phenyl)-7- benzylamine 1 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 411 hydroxy-1H-benzoimidazole-4- 7.37–7.23(4H, m), 6.92(1H, d), 4.68(2H, s) carboxylic acid benzylamide  56 3 2-(2,4-Dichloro-phenyl)-7- 4-nitrobenzylamine 1 δ 8.20(2H, d), 7.90(2H, t), 7.88(1H, s), 456 hydroxy-1H-benzoimidazole-4- 7.69–7.51(3H, m), 6.91(1H, d), 4.76(2H, s) carboxylic acid(4-nitro- benzyl)-amide  57 1 7-hydroxy-2-phenyl-1H-benzo- phenethylamine 2 δ 8.10(2H, d), 7.78(1H, d), 7.77–7.58(3H, m), 357 imidazole-4-carboxylic acid- 7.44–7.18(5H, m), 6.85(1H, s), 3.68(2H, t), phenethyl-amide 2.98(2H, t)  58 1 7-hydroxy-2-phenyl-1H-benzo- 4-hydroxyphenethylamine 2 δ 8.02–7.92(2H, m), 7.77(1H, d), 7.62–7.42(3H, 373 imidazole-4-carboxylic acid(4- m), 7.11(2H, d), 6.78(1H, d), 6.70(2H, d), hydroxy-pheneethyl)-amide 3.72(2H, t), 2.83(2H, t)  59 1 7-hydroxy-2-phenyl-1H-benzo- 4-nitrophenethylamine 2 δ 8.10(2H, d), 8.01(2H, d), 7.75(1H, d), 402 imidazole-4-carboxylic acid(4- 7.69–7.52(3H, m), 7.50(2H, d), 6.85(1H, d), nitro-phenethyl)-amide 3.75(2H, t), 3.08(2H, t)  60 1 7-hydroxy-2-phenyl-1H-benzo- 4-aminophenethylamine 2 δ 8.11(2H, d), 7.78(1H, d), 7.74–7.59(3H, m), 372 imidazole-3-carboxylic acid(4- 7.46(2H, d), 7.31(2H, d), 6.85(1H, d), 3.72(2H, amino-phenethyl)-amino t), 3.02(2H, t)  61 1 7-hydroxy-2-phenyl-1H-benzo- ethylenediamine 2 δ 7.95–7.70(2H, m), 7.69(1H, d), 7.60–7.42(1H, 296 imidazole-3-carboxylic acid(2- m), 7.41–7.23(2H, m), 3.77(2H, t), 3.25(2H, t) amino-ethyl)-amide  62 1 7-hydroxy-2-phenyl-1H-benzo- 4-hydroxy-3-methoxy- 2 δ 8.10–8.00(2H, m), 7.78(1H, d), 7.69–7.52(3H, 403 imidazole-3-carboxylic acid(4- phenethylamine m), 6.91–6.77(2H, m), 6.72(2H, d), 3.73(3H, s), hydroxy-3-methoxy-phenethyl)- 3.70(2H, t), 2.89(2H, t) amide  63 1 7-hydroxy-2-phenyl-1H-benzo- 3-hydroxy-4-methoxy- 2 δ 8.08–7.93(2H, m), 7.78(1H, d), 7.62–7.50(2H, 403 imidazole-4-carboxylic acid(3- phenethylamine m), 6.98–6.52(5H, m), 3.80(3H, s), 3.68(2H, t), hydroxy-4-methoxy-phenethyl)- 2.82(2H, t) amide  64 1 7-hydroxy-2-phenyl-1H-benzo- N-[4-(2-amino-ethyl)- 2 δ 8.07(1H, d), 7.77(1H, d), 7.65–7.61(4H, m), 450 imidazole-4-carboxylic acid[2- phenyl]-methane- 7.28(2H, d), 7.18(2H, d), 6.85(1H, d), 3.71(2H, (4-methanesulfonylamino- sulfonamide t), 2.95(2H, t), 2.85(3H, s) phenyl)-ethyl]-amide  65 1 7-hydroxy-2-phenyl-1H-benzo- N-[4-(2-amino-ethyl)- 2 δ 8.09(2H, d), 7.76–7.54(5H, m), 7.33–7.30(3H, 526 imidazole-4-carboxylic acid{2- phenyl]-4-methyl- m), 7.20–7.13(2H, m), 7.01–6.87(3H, m), [4-(toluene-4-sulfonylamino)- benzenesulfonamide 3.73(1H, t), 3.63(1H, t), 3.01(1H, t), 2.88(1H, phenyl]-ethyl}-amide t), 2.44(3H, s)  66 1 7-hydroxy-2-phenyl-H-benzo- 4-(2-aminoethyl)- 2 δ 8.17–8.12(2H, m), 7.88(1H, d), 7.77–7.71(3H, 366 imidazole-4-carboxylic acid(2- morpholine m), 7.00–6.95(1H, m), 4.02–3.75(4H, m), morpholin-4-yl-ethyl)-amide 3.89(2H, t), 3.47(2H, t), 3.46–3.00(4H, t)  67 1 7-hydroxy-2-phenyl-1H-benzo- 2-[4-(2-amino-ethyl)- 2 δ 8.14(2H, d), 7.97–7.68(8H, m), 7.40(4H, dd), 502 imidazole-4-carboxylic acid{2- phenyl]-isoindole-1,3-dione 6.93(1H, d), 3.74(2H, t), 3.05(2H, t) [4-(1,3-dioxo-1,3-dihydro-iso- indole-2-yl)-phenyl]-ethyl}- amide  68 1 7-hydroxy-2-phenyl-1H-benzo- N-[4-(2-amino-ethyl)- 2 δ 8.15(2H, d), 7.79–7.72(4H, m), 7.22(4H, dd), imidazole-4-carboxylic acid[2- phenyl]-ethanesulfomamide 6.97(1H, d), 3.66(2H, t), 2.99(2H, q), 2.89(2H, t), (4-ethanesulfonylamino-phenyl)- 1.22(3H, t) ethyl]-amide  69 1 7-hydroxy-2-phenyl-1H-benzo- 2-(2-aminoethylamino)-5- 2 δ 8.84(1H, d), 8.13–8.05(3H, m), 7.80–7.65(4H, 418 imidazole-4-carboxylic acid(5- nitropyridine m), 6.90(1H, d), 6.57(1H, d), 3.71–3.60(4H, m) mitropyridine-2-amino-ethyl)- amide  70 1 7-hydroxy-2-phenyl-1H-benzo- 2-(2-aminoethyl)- 2 8.71(1H, d), 8.44(1H, t), 8.13–7.99(4H, m), 358 imidazole-4-carboxylic acid(2- pyridine 7.85(1H, t), 7.76–7.70(2H, m), 6.99(1H, d), pyridine-2-yl-ethyl)-amide 6.83(1H, d), 3.97(2H, t), 3.42(2H, t)  71 2 2-(4-chloro-phenyl)-7-hydroxy- phenethylamine 2 δ 8.03(2H, d), 7.79(1H, d), 7.64(2H, m), 391 1H-benzoimidazole-4-carboxylic 7.37–7.15(5H, m), 6.84(1H, d), 3.75(2H, t), acid phenethyl amide 2.99(2H, t)  72 2 2-(4-chloro-phenyl)-7-hydroxy- 4-nitrophenethylamine 2 δ 8.18(2H, d), 8.05(2H, d), 7.80(1H, d), 7.64(2H, 436 1H-benzoimidazole-4-carboxylic d), 7.56(2H, d), 6.88(1H, d), 3.80(2H, t), acid(4-nitro-phenethyl)-amide 3.11(2H, t)  73 2 2-(4-chloro-phenyl)-7-hydroxy- 4-aminophenethylamine 2 δ 8.11(2H, d), 7.83(1H, d), 7.64(2H, d), 7.50(2H, 406 1H-benzoimidazole-4-carboxylic d), 7.31(2H, d), 6.82(1H, d), 3.78(2H, t), acid(4-amino-phenethyl)-amide 3.07(2H, t)  74 2 2-(4-chloro-phenyl)-7-hydroxy- 4-hydroxyphenethylamine 2 δ 7.82(1H, d), 7.73(2H, d), 7.65(2H, d), 407 1H-benzoimidazole-4-carboxylic 7.12(2H, d), 7.00(1H, d), 6.86(1H, d), 6.74(1H, acid(4-hydroxy-phenethyl)- d), 3.71(2H, t), 2.87(2H, t) amide  75 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl- 2 δ 8.08(2H, d), 7.79(1H, d), 7.69(2H, d), 484 1H-benzoimidazole-4-carboxylic phenyl)-methane- 7.29–7.16(4H, dd), 6.89(1H, d), 3.71(2H, t), acid[2-(4-methanesulfonyl- sulfonamide 2.95(2H, t), 2.88(3H, s) amino-phenyl)-ethyl]-amide  76 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.08(2H, d), 7.77(1H, d), 7.69(2H, d), 7.55(1H, 560 1H-benzoimidazole-4-carboxylic phenyl]-4-methyl- d), 7.15(3H, m), 6.98(2H, d), 6.88(1H, d), acid{2-[4-(toluene-4- benzenesulfonamide 3.65(2H, t), 2.86(2H, t), 2.31(3H, s) sulfonylamino)-phenyl]-ethyl}- amine  77 2 2-(4-chloro-phenyl)-7-hydroxy- 3-hydroxy-4-methoxy- 2 δ 8.10–7.37(3H, m), 7.36–6.43(6H, m), 437 1H-benzoimidazole-4-carboxylic phenethylamine 3.72(3H, s), 3.70(2H, t), 2.81(2H, t) acid(3-hydroxy-4-methoxy- phenethyl)-amide  78 2 2-(4-chloro-phenyl)-7-hydroxy- 4-(2-aminoethyl) 2 δ 8.16(2H, d), 7.88(1H, d), 7.70(2H, d), 6.94(1H, 400 1H-benzoimidazole-4-carboxylic morpholine d), 4.14–3.92(2H, m), 3.90(2H, t), 3.89–3.72(2H, acid(2-morpholin-4-yl-ethyl)- m), 3.84–3.57(2H, m), 3.48(2H, t), amide 3.30–3.04(2H, m)  79 2 2-(4-chloro-phenyl)-7-hydroxy- 2-[4-(2-amino-ethyl)- 2 δ 8.10(2H, d), 7.91–7.85(4H, m), 7.80(1H, d), 536 1H-benzoimidazole-4-carboxylic phenyl]-isoindole-1,3- 7.68(2H, m), 6.98(1H, d), 7.40(4H, dd), 6.93(1H, acid-2-[4-(1,3-dioxo-1,3- dione m), 3.75(2H, t), 3.07(2H, t) dihydro-isoindole-2-yl)-phenyl]- ethyl-amide  80 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl- 2 δ 8.13–8.05(3H, m), 7.80–7.65(3H, m), 498 1H-benzoimidazole-4-carboxylic phenyl]-ethane- 7.28–7.16(4H, m), 3.69(2H, t), 2.99(2H, q), acid[2-(4-ethanesulfonyl- sulfonamide 2.89(2H, t), 1.28(3H, t) amino-phenyl)-ethyl]-amide  81 2 2-(4-chloro-phenyl)-7-hydroxy- 2-(2-aminoethylamino)-5- 2 δ 8.83(1H, d), 8.11–8.05(1H, m), 7.86–7.81(3H, 452 1H-benzoimidazole-4-carboxylic nitropyridine m), 7.68–7.60(2H, m), 6.90(1H, d), acid(5-nitropyridine-2-amino- 6.60–6.54(1H, d), 3.71–3.60(4H, m) ethyl)-amide  82 2 2-(4-chloro-phenyl)-7-hydroxy- 2-(2-aminoethyl)- 2 δ 8.70(1H, d), 8.43(1H, t), 8.13–8.09(3H, m), 392 1H-benzoimidazole-4-carboxylic pyridine 8.01(1H, d), 7.94(1H, d), 7.77(1H, d), 7.61(2H, acid(2-pyridine-2-yl-ethyl)- d), 4.01(2H, t), 3.42(2H, t) amide  83 2 2-(4-chloro-phenyl)-7-hydroxy- histamine 2 δ 8.81(s, 1H), 8.12(d, 2H), 7.80(d, 1H), 7.65(d, 1H-benzoimidazole-4-carboxylic 2H), 7.40(s, 1H), 6.83(d, 1H), 3.84(t, 2H), acid[2-(1H-imidazol-4-yl)- 3.12(t, 2H) ethyl]amine  84 2 2-(4-chloro-phenyl)-7-hydroxy- 4-hydroxyphenethylamine 2 δ 8.05(d, 2H), 7.79(d, 1H), 7.65(d, 2H), 7.12(d, 1H-benzoimidazole-4-carboxylic 2H), 6.85(d, 1H), 6.72(d, 2H), 3.70(t, 2H), acid[2-(4-hydroxy-phenyl)- 2.87(t, 2H) ethyl]-amide  85 2 2-(4-Chloro-phenyl)-7-hydroxy- 4-acetyl-2-pyridiylethyl 2 δ 8.57(s, 1H), 8.20~8.00(m, 3H), 8.02(br, 1H), 1H-benzoimidazole-4-carboxylic amine 7.75~7.60(m, 3H), 7.38(d, 1H), 6.88(d, 1H), acid[2-(5-acetylamino- 4.12(t, 2H), 3.68(t, 2H), 2.12(s, 3H) pyridin-2-ylamino)-ethyl]-amide  86 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(m, 2H), 7.80(d, 1H), 7.60(d, 2H), 7.57(d, 1H-benzoimidazole-4-carboxylic phenyl]-2-(4-methyl- 2H), 7.29(d, 2H), 6.83(d, 1H), 3.75(t, 2H), acid(2-{4-[2-(4-methyl- piperazin-1-yl)- 3.34(s, 2H), 3.10~2.75(m, 13H) piperazin-1-yl)-acetyl-amino]- acetamide phenyl}-ethyl)-amide  87 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(m, 2H), 7.79(d, 1H), 7.61(d, 2H), 7.53(d, 1H-benzoimidazole-4-carboxylic phenyl]-2-(4-ethyl- 2H), 7.29(d, 2H), 6.84(d, 1H), 3.75(t, 2H), acid(2-{4-[2-(4-ethyl- piperazin-1-yl)-acetamide 3.34(s, 2H), 3.25(q, 2H), 3.05~2.75(m, 8H), piperazin-1-yl)-acetylamino]- 1.35(t, 3H phenyl}-ethyl)-amide  88 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(d, 2H), 7.80(d, 1H), 7.60(d, 2H), 7.54(t, 1H-benzoimidazole-4-carboxylic phenyl]-2-dimethyl- 2H), 7.32(d, 2H), 6.81(d, 1H), 4.08(s, 2H), acid{2-[4-(2-dimethylamino- amino-acetamide 3.76(t, 2H), 2.95(m, 8H) acetylamino)-phenyl]-ethyl}- amide  89 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.02(d, 2H), 7.80(d, 1H), 7.60(d, 2H), 7.54(d, 1H-benzoimidazole-4-carboxylic phenyl]-2-diethylamino- 2H), 7.32(d, 2H), 6.81(d, 1H), 4.06(s, 2H), acid{2-[4-(2-diethylamino- acetamide 3.77(t, 2H), 3.32(q, 4H), 2.99(t, 2H), 1.35(t, 6H) acetylamino)-phenyl]-ethyl}- amide  90 2 2-(4-chloro-phenyl)-7-hydroxy- 4-aminophenethylamine 2 δ 8.13(d, 2H), 7.78(d, 1H), 7.62(d, 2H), 7.51(d, 1H-benzoimidazole-4-carboxylic 2H), 7.29(d, 2H), 6.77(d, 1H), 3.79(t, 2H), acid[2-(4-amino-phenyl)- 3.69(t, 2H ethyl]-amide  91 2 2-(4-chloro-phenyl)-7-hydroxy- N-(2-amino-ethyl)- 2 δ 8.73(s, 1H), 8.22(d, 1H), 8.09(d, 1H), 7.88(m, 1H-benzoimidazole-4-carboxylic pyridine-2,5-diamine 2H), 7.60(d, 1H), 7.47(d, 1H), 7.13(d, 1H), acid[2-(5-amino-pyridin-2- 6.78(m, 1H), 3.87(t, 2H), 3.75(t, 2H) ylamino)-ethyl]-amide  92 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(d, 2H), 7.80(d, 1H), 7.60(d, 2H), 7.54(d, 1H-benzoimidazole-4-carboxylic phenyl]-2-morpholin-4- 2H), 7.31(d, 2H), 6.81(d, 1H), 3.12(s, 2H), acid{2-[4-(2-morpholin-4-yl- yl-acetamide 3.98(br, 4H), 3.77(t, 2H), 3.44(br, 4H), 2,98(t, acetylamino)-phenyl]-ethyl}- 2H) amide  93 2 2-(4-chloro-phenyl)-7-hydroxy- N,N-(dimethylamino)- 2 δ 8.13(d, 2H), 7.78(d, 1H), 7.62(d, 2H), 7.51(d, 1H-benzoimidazole-4-carboxylic phenethylamine 2H), 7.29(d, 1H), 6.77(d, 1H), 3.81(t, 2H), acid[2-(4-dimethylamino- 3.15(s, 6H), 3.08(t, 2H) phenyl)-ethyl]-amide  94 2 2-(4-chloro-phenyl)-7-hydroxy- 2-[4-(2-morpholin-4-yl- 2 δ 8.06(d, 2H), 7.79(d, 1H), 7.73(d, 2H), 7.28(d, 1H-benzoimidazole-4-carboxylic ethoxy)-phenyl]- 2H), 6.94(d, 2H), 6.83(d, 1H), 4.31(m, 2H), acid{2-[4-(2-morpholin-4-yl- ethylamine 3.99(br, 2H), 3.95~3.65(m, 4H), 3.65~3.50(m, ethoxy)phenyl]-ethyl}-amide 4H), 3.32(m, 2H), 2.95(m, 2H)  95 2 2-(4-chloro-phenyl)-7-hydroxy- 2-{4-[2-(4-methyl- 2 δ 8.17(d, 2H), 7.78(d, 1H), 7.40(t, 2H), 7.23(d, 1H-benzoimidazole-4-carboxylic piperazin-1-yl)-ethoxy]- 2H), 6.90(m, 3H), 4.25(t, 2H), 3.67(t, 2H), acid(2-{4-]2-(4-methyl- phenyl}-ethylamine 3.50~3.30(m, 10H), 2.90(m, 5H) piperazin-1-yl)ethoxy]-phenyl}- ethyl)-amide  96 2 2-(4-chloro-phenyl)-7-hydroxy- 2-hydroxyphenethyl- 2 δ 8.05(d, 2H), 7.79(d, 1H), 7.62(d, 2H), 7.18(d, 1H-benzoimidazole-4-carboxylic amine 1H), 07.05(d, 1H), 6.90~6.70(m, 3H), 3.70(t, acid[2-(2-hydroxy-phenyl)- 2H), 3.02(t, 2H) ethyl]-amide  97 2 2-(4-chloro-phenyl)-7-hydroxy- 2-methoxyphenethylamine 2 δ 8.00(d, 2H), 7.81(d, 1H), 7.57(d, 2H), 7.24(d, 1H-benzoimidazole-4-carboxylic 1H), 6.95(m, 1H), 6.85(m, 1H), 6.73(d, 2H), acid[2-(2-methoxy-phenyl)- 3.76(s, 3H), 3.64(t, 2H), 2.98(t, 2H) ethyl]-amide  98 2 2-(4-chloro-phenyl)-7-hydroxy- 3-bromophenethylamine 2 δ 8.00(d, 2H), 7.79(d, 1H), 7.02~7.50(m, 3H), 1H-benzoimidazole-4-carboxylic 7.40~7.20(m, 3H), 6.74(d, 1H), 3.81(t, 2H), acid[2-(3-bromo-phenyl)- 3.01(t, 2H) ethyl]-amide  99 3 2-(2,4-dichloro-phenyl)-7- phenethylamine 2 δ 7.92–7.66(3H, m), 7.65–7.38(1H, m), 425 hydroxy-1H-benzoimidazole-4- 7.37–7.00(5H, m), 7.44–7.18(5H, m), 6.85(1H, carboxylic acid phenethyl-amide d), 3.68(2H, t), 2.98(2H, t) 100 3 2-(2,4-dichloro-phenyl)-7- 4-nitrophenethylamine 2 δ 8.08(2H, d), 7.90–7.31(5H, m), 7.20–6.97(1H, 470 hydroxy-1H-benzoimidazole-4- m), 6.82(1H, d), 3.76(2H, t), 3.09(2H, t) carboxylic acid(4-amino- phenethyl)-amide 101 3 2-(2,4-dichloro-phenyl)-7- 4-hydroxy-3-methoxy- 2 δ 7.95–7.68(3H, m), 7.67–7.40(2H, m), 471 hydroxy-1H-benzoimidazole-4- phenethylamine 7.20–6.92(1H, m), 6.82(2H, t), 6.68(1H, d), carboxylic acid(4-hydroxy-3- 3.72(2H, t), 3.60(3H, s), 2.88(2H, t) methoxy-phenethyl)-amide 102 3 2-(2,4-dichloro-phenyl)-7- 3-hydroxy-4-methoxy- 2 δ 8.10–7.37(3H, m), 7.36–6.43(6H, m), 3.72(3H, 471 hydroxy-1H-benzoimidazole-4- phenethylamine s), 3.70(2H, t), 2.81(2H, t) carboxylic acid(3-hydroxy-4- methoxy-phenethyl)-amide 103 3 2-(2,4-dichloro-phenyl)-7- ethylenediamine 2 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 364 hydroxy-1H-benzoimidazole-4- 7.37–7.23(4H, m), 6.92(1H, d), 3.77(2H, t), carboxylic acid(2-amino-ethyl)- 3.25(2H, t) amide 104 3 2-(2,4-dichloro-phenyl)-7- 4-hydroxyphen- 2 δ 7.94–7.64(3H, m), 7.62–7.39(1H, m), 441 hydroxy-1H-benzoimidazole-4- ethylamine 7.28–6.97(3H, m), 6.96–6.78(1H, m), 6.68(1H, carboxylic acid(4-hydroxy- d), 3.64(2H, t), 2.82(2H, t) phenethyl)-amide 105 3 2-(2,4-dichloro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.95–7.70(2H, m), 7.69–7.43(3H, m), 594 hydroxy-1H-benzoimidazole-4- phemphenyl]-4-methyl- 7.42–7.23(3H, m), 7.22–7.03(2H, m), 7.01(1H, carboxylic acid{2-[4- benzenesulfonamide d), 6.98–6.77(2H, m), 3.81–3.52(2H, m), (toluene-4-sulfonylamino)- 3.10–2.73(2H, m), 3.01(1H, t), 2.88(1H, t), phenyl]-ethyl}-amide 2.48(3H, s) 106 3 2-(2,4-dichloro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.92–7.78(3H, m), 7.68(1H, d), 7.24(4H, dd), 518 hydroxy-1H-benzoimidazole-4- phenyl]-methane 6.96(1H, d), 3.68(2H, t), 2.93(2H, t), 2,90(3H, s) carboxylic acid[2-(4-methane- sulfonamide sulfonylamino-phenyl)-ethyl]- amide 107 3 2-(2,4-dichloro-phenyl)-7- 2-[4-(2-amino-ethyl)- 2 δ 7.92–7.83(7H, m), 7.67(1H, d), 7.38(4H, dd), 570 hydroxy-1H-benzoimidazole-4- phenyl]-isoindole-1,3- 6.98(1H, d), 3.72(2H, t), 3.05(2H, t) carboxylic acid{2-[4-(1,3- dione dioxo-1,3-dihydro-isoindole-2- yl)-phenyl]-ethyl}-amide 108 3 2-(2,4-dichloro-phenyl)-7- 4-(2-aminoethyl)- 2 δ 8.02–7.80(3H, m), 7.65(1H, d), 6.98(1H, d), 434 hydroxy-1H-benzoimidazole-4- morpholine 4.14–3.92(2H, m), 3.88(2H, t), 3.89–3.72(2H, carboxylic acid(2-morpholin-4- m), 3.84–3.57(2H, m), 3.44(2H, t), yl-ethyl)-amide 3.30–3.04(2H, m) 109 3 2-(2,4-dichloro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.91–7.75(3H, m), 7.68(1H, d), 7.21(4H, dd), 532 hydroxy-1H-benzoimidazole-4- phenyl]-ethanesulfonamide 6.99(1H, d), 3.66(2H, t), 2.99(2H, q), 2.89(2H, t), carboxylic acid[2-(4- 1.28(3H, t) ethanesulfonylamino-phenyl)- ethyl]-amide 110 3 2-(2,4-dichloro-phenyl)-7- 2-(2-aminoethylamino)- 2 δ 8.83(1H, d), 8.11–8.05(1H, m), 7.86–7.81(3H, 486 hydroxy-1H-benzoimidazole-4- 5-nitropyridine m), 7.68–7.60(1H, m), 6.90(1H, d), carboxylic acid(5-nitropyridine- 6.60–6.54(1H, d), 3.71–3.60(4H, m) 2-amino-ethyl)-amide 111 3 2-(2,4-dichloro-phenyl)-7- 2-(2-aminoethyl)-pyridine 2 δ 8.70(1H, d), 8.40(1H, t), 8.07–7.50(6H, m), 426 hydroxy-1H-benzoimidazole-4- 6.83(1H, d), 3.95(2H, t), 3.38(2H, t) carboxylic acid(2-pyridin-2-yl- ethyl)-amide 112 3 2-(2,4-dichloro-phenyl)-7- 4-(acetylamino)phen- 2 δ 7.85~7.78(m, 3H), 7.61(d, 1H), 7.25(d, 2H), hydroxy-1H-benzoimidazole-4- ethylamine 7.15(d, 2H), 6.86(d, 1H), 3.69(t, 2H), 2.95(t, carboxylic acid[2-(4-acetyl- 2H), 2.88(s, 3H) amino-phenyl)-ethyl]-amide 113 3 2-(2,4-dichloro-phenyl)-7- 4-(pentanoylamino)- 2 δ 7.90~7.80(m, 3H), 7.72(d, 1H), 7.61(d, 2H), hydroxy-1H-benzoimidazole-4- phenethylamine 7.20(d, 2H), 6.89(d, 1H), 3.68(t, 2H), 2.89(t, 2H), carboxylic acid[2-(4-pentanoyl- 2.35(t, 2H), 1.65(m, 2H), 1.38(m, 2H), 0.96(t, amino-phenyl)ethyl]-amide 3H) 114 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.15–8.10(2H, m), 7.78(1H, d), 7.46(2H, t), hydroxy-1H-benzoimidazole-4- phenyl]-methane- 7.27(2H, d), 7.18(2H, d), 6.87(1H, d), 3.70(2H, carboxylic acid[2-(4-methane- sulfonamide t), 2.97(2H, t), 2.87(3H, s) sulfonylamino-phenyl)-ethyl]- amide 115 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 hydroxy-1H-benzoimidazole-4- phenyl]-p-toluene- carboxylic acid{2-[4-(toluene- sulfonamide 4-sulfonylamino)phenyl]- ethyl}-amide 116 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.17(2H, m), 7.77(1H, d), 7.44(2H, t), 7.25(2H, hydroxy-1H-benzoimidazole-4- phenyl]-ethane- d), 7.17(2H, d), 6.92(1H, d), 3.67(2H, t), carboxylic acid[2-(4-ethane- sulfonamide 3.02(2H, q), 2.96(2H, t), 1.26(3H, t) sulfonylamino-phenyl)-ethyl]- amide 117 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.1~8.2(m, 2H), 7.58(d, 1H), 7.44(m, 4H), hydroxy-1H-benzoimidazole-4- phenyl]-acetamide 7.34(m, 2H), 6.92(d, 1H), 3.66(t, 2H), 2.90(t, carboxylic acid[2-(4-acetyl- 2H), 2.09(s, 1H) amino-phenyl)-ethyl]-amide 118 4 2-(4-fluoro-phenyl)-7- 2-(4-methyl-piperazin-1- 2 δ 8.25~8.16(m, 2H), 8.05(d, 1H), 7.48~7.37(m, hydroxy-1H-benzoimidazole-4- yl)-ethylamine 2H), 6.88(d, 1H), 3.70~3.50(m, 10H), 3.14(t, carboxylic acid[2-(4-methyl- 2H), 2.96(s, 3H), 2.12(t, 2H) piperazin-1-yl)-ethyl]-amide 119 4 2-(4-fluoro-phenyl)-7- 2-morpholin-4-yl- 2 δ 8.22(m, 2H), 7.85(d, 1H), 7.41(t, 2H), 6.90(d, hydroxy-1H-benzoimidazole-4- ethylamine 1H), 4.20~3.60(m, 8H), 3.48(t, 2H), carboxylic acid(2-morpholin-4- 3.34~3.10(br, 2H) yl-ethyl)-amide 120 4 2-(4-fluoro-phenyl)-7- pentanoic acid 2 δ 8.08(m, 2H), 7.74(d, 1H), 7.45( d, 2H), 7.35(t, hydroxy-1H-benzoimidazole-4- [4-(2-amino-ethyl)- 2H), 7.18(d, 2H), 6.86(d, 1H), 3.66(t, 2H), 2.86(t, carboxylic acid[2-(4-pentanoyl- phenyl]-amide 2H), 2.33(t, 2H), 1.64(m, 2H), 1.39(m, 2H), amino-phenyl)-ethyl]-amide 0.93(t, 3H) 121 4 2-(4-fluoro-phenyl)-7- 4-hydroxyphenethylamine 2 δ 8.14(m, 2H), 7.78(d, 1H), 7.44(t, 2H), 7.09(d, hydroxy-1H-benzoimidazole-4- 2H), 6.89(d, 1H), 6.72(d, 2H), 3.66(t, 2H), carboxylic acid[2-(4-hydroxy- 2.86(t, 2H) phenyl)-ethyl]-amide 122 4 2-(4-fluoro-phenyl)-7- N-(4-nitro-pyridin-2- 2 δ 8.84(s, 1H), 8.21~8.17(m, 3H), 7.79(d, 1H), hydroxy-1H-benzoimidazole-4- yl)-ethane-1,2-diamine 7.44(t, 2H), 6.92(d, 1H), 6.63(br, 1H), carboxylic acid[2-(5-nitro- 3.90~3.60(m, 4H) pyridin-2-ylamino)-ethyl]-amide 123 4 2-(4-fluoro-phenyl)-7- N-[6-(2-Amino-ethyl- 2 δ 8.24~8.19(m, 2H), 7.95~7.75(m, 3H), 7.43(t, hydroxy-1H-benzoimidazole-4- amino)-pyridin-3-yl]- 2H), 7.15(d, 1H), 6.92(d, 1H), 3.80~3.65(m, 4H), carboxylic acid[2-(5-methane- methanesulfonamide 2.99(t, 3H) sulfonylamino-pyridin-2- ylamino)-ethyl]-amide 124 4 2-(4-fluoro-phenyl)-7- N-[6-(2-amino-ethylamino)- 2 δ 8.23(m, 2H), 7.81(d, 1H), 7.52(m, 4H), hydroxy-1H-benzoimidazole-4- pyridin-3-yl]-p- 7.40~7.20(m, 4H), 7.01(d, 1H), 6.82(d, 1H), carboxylic acid{2-[5-(toluene- toluenesulfonamide 3.75(t, 2H), 3.66(t, 2H), 2.36(s, 3H) 4-sulfonylamino)-pyridin-2- ylamino]-ethyl}-amide 125 4 2-(4-fluoro-phenyl)-7- histamine 2 δ0 8.81(s, 1H), 8.19(m, 2H), 7.80(d, 1H), hydroxy-1H-benzoimidazole-4- 7.50~7.30(m, 3H), 6.90(d, 1H), 3.80(t, 2H), carboxylic acid[2-(1H-imidazol- 3.11(t, 2H) 4-yl)-ethyl]-amide 126 4 2-(4-fluoro-phenyl)-7- N-[6-(2-amino-ethylamino)- 2 δ 8.58(s, 1H), 8.22(m, 2H), 8.04(br, 1H), 7.69(d, hydroxy-1H-benzoimidazole-4- pyridin-3-yl]-acetamide 1H), 7.50~7.35(m, 3H), 6.90(d, 1H), 4.11(t, 2H), carboxylic acid[2-(5-acetyl- 3.69(t, 2H), 2.11(s, 3H) amino-pyridin-2-yl-amino)- ethyl]-amide 127 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.10~7.80(m, 2H), 7.69(d, 1H), 7.43(d, 2H), hydroxy-1H-benzoimidazole-4- phenyl]-2-(4-methyl- 7.25(t, 2H), 7.19(d, 2H), 6.76(d, 1H), 3.63(t, 2H), carboxylic acid(2-{4-[2-(4- piperazin-1-yl)-acetamide 3.21(s, 2H), 2.90~2.78(m, 13H) methyl-piperazin-1-yl)-acetyl- amino]-phenyl}-ethyl)-amide 128 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.13(m, 2H), 7.79(d, 1H), 7.52(d, 2H), 7.37(t, hydroxy-1H-benzoimidazole-4- phenyl]-2-(4-ethyl- 2H), 7.27(d, 2H), 6.85(d, 1H), 3.72(t, 2H), carboxylic acid(2-{4-[2-(4- piperazin-1-yl)-acetamide 3.30(s, 2H), 3.24(q, 2H), 3.05~2.85(m, 10H), ethyl-piperazin-1-yl)-acetyl- 1.35(t, 3H) amino]-phenyl}-ethyl)-amide 129 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.11(m, 2H), 7.78(d, 1H), 7.53(d, 2H), hydroxy-1H-benzoimidazole-4- phenyl]-2-dimethyl- 7.40~7.25(m, 4H), 6.83(d, 1H), 4.09(s, 2H), carboxylic acid{2-[4-(2- amino-acetamide 3.74(t, 2H), 2.94(m, 8H) dimethylamino-acetylamino)- phenyl]-ethyl}-amide 130 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.13(m, 2H), 7.79(d, 1H), 7.54(d, 2H), 7.39(t, hydroxy-1H-benzoimidazole-4- phenyl]-2-diethyl- 2H), 7.30(d, 2H), 6.86(d, 1H), 4.08(s, 2H), carboxylic acid{2-[4-(2- amino-acetamide 3.72(t, 2H), 3.33(q, 4H), 2.96(t, 2H), 1.35(t, 6H) diethylamino-acetylamino)- phenyl]-ethyl}-amide 131 4 2-(4-fluoro-phenyl)-7- 4-aminophenethylamine 2 δ 8.20(m, 2H), 7.79(d, 1H), 7.49(d, 2H), 7.42(t, hydroxy-1H-benzoimidazole-4- 2H), 7.32(d, 2H), 6.86(d, 1H), 3.74(t, 2H), carboxylic acid[2-(4-amino- 3.06(t, 2H) phenyl)-ethyl]-amide 132 4 2-(4-fluoro-phenyl)-7- 2-(4-morpholin-4-yl- 2 δ 8.14(m, 2H), 7.78(d, 1H), 7.41(d, 2H), 7.35(d, hydroxy-1H-benzoimidazole-4- phenyl)-ethylamine 1H), 7.14(d, 2H), 6.85(d, 1H), 3.89(m, 4H), carboxylic acid[2-(4- 3.71(t, 2H), 3.28(m, 4H), 2.96(t, 2H) morpholin-4-yl-phenyl)- ethyl]-amide 133 4 2-(4-fluoro-phenyl)-7- {1-[4-(2-amino-ethyl)- 2 δ 8.13(m, 1H), 7.78(d, 1H), 7.32~7.20(m, 4H), hydroxy-1H-benzoimidazole-4- phenyl]-pyrrolidin-3-yl}- 7.11(s, 1H), 6.74(m, 2H), 6.48(d, 1H), 3.60(t, carboxylic acid{2-[4-(3- diethyl-amine 2H), 2.90(t, 2H), 2.82~2.71(m, 6H), 2.40(q, diethylamino-pyrrolidin-1-yl)- 4H), 1.65(m, 1H), 1.02(t, 6H) phenyl]-ethyl}-amide 134 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.15(m, 2H), 7.79(d, 1H), 7.53(d, 2H), 7.39(t, hydroxy-1H-benzoimidazole-4- phenyl]-2-morpholin-4- 2H), 7.29(d, 2H), 6.87(d, 1H), 4.13(s, 2H), carboxylic acid{2-[4-(2- yl-acetamide 3.97(br, 4H), 3.72(q, 2H), 3.44(br, 4H), 2.97(t, morpholin-4-yl-acetylamino)- 2H) phenyl]-ethyl}-amide 135 4 2-(4-fluoro-phenyl)-7- N,N-(dimethylamino)- 2 δ 8.20(m, 3H), 7.78(d, 1H), 7.54(m, 3H), 7.43(t, hydroxy-1H-benzoimidazole-4- phenethylamine 2H), 6.84(d, 1H), 3.75(t, 2H), 3.21(s, 6H), carboxylic acid[2-(4-dimethyl- 3.07(t, 2H) amino-phenyl)-ethyl]-amide 136 4 2-(4-fluoro-phenyl)-7- 2-[4-(2-morpholin-4-yl- 2 δ 8.18(m, 2H), 7.79(d, 1H), 7.42(t, 2H), 7.26(d, hydroxy-1H-benzoimidazole-4- ethoxy)phenyl]- 2H), 7.00~6.85(m, 3H), 4.33(m, 2H), carboxylic acid{2-[4-(2- ethylamine 4.10~4.00(br, 2H), 3.95~3.75(br, 2H), morpholin-4-yl-ethoxy)-phenyl]- 3.75~3.50(m, 8H), 3.32(m, 4H), 2.95(m, 2H) ethyl}-amide 137 4 2-(4-fluoro-phenyl)-7- 2-hydroxyphenethylamine 2 δ 8.18(m, 2H), 7.78(d, 1H), 7.38(t, 2H), 7.14(d, hydroxy-1H-benzoimidazole-4- 1H), 7.03(d, 1H), 6.88~6.74(m, 3H), 3.77(t, 2H), carboxylic acid[2-(2-hydroxy- 2.98(t, 2H) phenyl)-ethyl]-amide 138 4 2-(4-fluoro-phenyl)-7- 2-methoxyphen- 2 δ 8.18~8.05(m, 2H), 7.78(d, 1H), 7.45~7.25(m, hydroxy-1H-benzoimidazole-4- ethylamine 3H), 7.20(m, 2H), 6.95(d, 1H), 6.82(d, 1H), carboxylic acid[2-(2-methoxy- 3.78(s, 3H), 3.73(t, 2H), 2.99(t, 2H) phenyl)-ethyl]-amide 139 4 2-(4-fluoro-phenyl)-7- 3-bromophenethylamine 2 δ 8.12(m, 2H), 7.80(d, 1H), 7.49(s, 1H), hydroxy-1H-benzoimidazole-4- 7.38~7.18(m, 5H), 6.83(d, 1H), 3.76(t, 2H), carboxylic acid[2-(3-bromo- 2.97(t, 2H) phenyl)-ethyl]-amide 140 5 2-(2,4-difluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.92–7.89(1H, m), 7.74(1H, m), 7.30–7.11(6H, hydroxy-1H-benzoimidazole-4- phenyl]-methane- m), 6.74(1H, d), 3.67(2H, bs), 2.89(2H, bs), carboxylic acid[2-(4-methane- sulfonamide 2.82(3H, s) sulfonylamino-phenyl)-ethyl]- amide 141 5 2-(2,4-difluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.99(1H, m), 7.74(1H, d), 7.50(2H, d), hydroxy-1H-benzoimidazole-4- phenyl]-p-toluene- 7.33–7.26(2H, m), 7.23(4H, m), 6.94(2H, d), carboxylic acid{2-[4-(toluene- sulfonamide 6.81(1H, d), 3.58(2H, t), 2.82(2H, t), 2.23(3H, s) 4-sulfonylamino)-phenyl]- ethyl}amide 142 5 2-(2,4-difluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.06(1H, d), 7.81(1H, d), 7.51–7.15(6H, m), hydroxy-1H-benzoimidazole-4- phenyl]-ethanesulfonamide 6.88(1H, d), 3.67(2H, t), 3.01(2H, q), 2.92(2H, carboxylic acid[2-(4-ethane- t), 1.25(3H, m) sulfonylamino-phenyl)-ethyl]- amide 143 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.94(1H, m), 7.84(1H, m), 7.62(1H, m), 7-hydroxy-1H-benzoimidazole- phenyl]-methane- 7.43(2H, m), 7.38–7.24(3H, m), 6.95(1H, d), 4-carboxylic acid[2-(4-methane- sulfonamide 3.65(2H, t), 2.99–2.83(5H, m) sulfonylamino-phenyl)-ethyl]- amide 144 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.91(1H, m), 7.81(1H, d), 7.62–7.54(3H, 7-hydroxy-1H-benzoimidazole- phenyl]-p-toluene- m), 7.42(1H, m), 7.20–7.11(4H, m), 4-carboxylic acid{2-[4- sulfonamide 7.05–6.93(3H, m), 3.61(2H, t), 2.86(2H, t), toluene-4-sulfonylamino)- 2.32(3H, s) phenyl]-ethyl}amide 145 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.83(2H, m), 7.56(1H, m), 7.36(1H, m), 7-hydroxy-1H-benzoimidazole- phenyl]-ethane- 7.18–7.11(4H, m), 7.38–7.24(3H, m), 6.92(1H, 4-carboxylic acid[2-(4- sulfonamide d), 3.60(2H, t), 2.99(4H, m), 1.23(3H, s) ethanesulfonylamino-phenyl)- ethyl]-amide 146 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 8.00~7.91(m, 2H), 7.57(d, 1H), 7.48~7.34(m, 7-hydroxy-1H-benzoimidazole- phenyl]-acetamide 3H), 7.19(d, 2H), 6.92(d, 1H), 3.66(t, 2H), 4-carboxylic acid[2-(4- 2.9(t, 2H), 2.09(s, 3H) acetylamino-phenyl)-ethyl]- amide 147 6 2-(2-chloro-4-fluoro-phenyl)- 2-morpholin-4-yl- 2 δ 8.00~7.90(m, 2H), 7.60(d, 1H), 7.43(t, 1H), 7-hydroxy-1H-benzoimidazole- ethylamine 6.95(d, 1H), 4.20~3.60(m, 8H), 3.46(t, 2H), 4-carboxylic acid(2-morpholin- 3.34~3.10(br, 2H) 4-yl-ethyl)-amide 148 6 2-(2-chloro-4-fluoro-phenyl)- 2-(4-methyl-piperazin-1- 2 δ 7.98(m, 2H), 7.59(d, 1H), 7.40(t, 1H), 6.93(d, 7-hydroxy-1H-benzoimidazole- yl)-ethylamine 1H), 3.80~3.50(br, 10H), 3.21(t, 2H), 2.95(s, 4-carboxylic acid[2-(4-methyl- 3H), 2.06(t, 2H) piperazin-1-yl)-ethyl]-amide 149 6 2-(2-chloro-4-fluoro-phenyl)- pentanoic acid 2 δ 7.92~7.82(m, 2H), 7.57(d, 1H), 7.46~7.37(m, 7-hydroxy-1H-benzoimidazole- [4-(2-amino-ethyl)- 3H), 7.20(d, 2H), 6.92(d, 1H), 3.66(t, 2H), 2.91(t, 4-carboxylic acid[2-(4- phenyl]-amide 2H), 2.34(t, 2H), 1.66(m, 2H), 1.40(m, 2H), pentanoylamino-phenyl)- 0.95(t, 3H) ethyl]-amide 150 6 2-(2-chloro-4-fluoro-phenyl)- 4-hydroxyphenethylamine 2 δ 7.92~7.83(m, 2H), 7.62(d, 1H), 7.43(t, 1H), 7-hydroxy-1H-benzoimidazole- 7.07(d, 2H), 6.94(d, 1H), 6.69(d, 2H), 3.62(t, 4-carboxylic acid[2-(4-hydroxy- 2H), 2.85(t, 2H) phenyl)-ethyl]-amide 151 6 2-(2-chloro-4-fluoro-phenyl)- N-(5-nitro-pyridin-2- 2 δ 8.85(s, 1H), 8.12(br, 1H), 7.79~7.85(m, 3H), 7-hydroxy-1H-benzoimidazole- yl)-ethane-1,2-diamine 7.63(d, 1H), 7.42(t, 1H), 6.95(d, 1H), 6.62(br, 4-carboxylic acid[2-(5-nitro- 1H), 3.90~3.60(m, 4H) pyridin-2-ylamino)-ethyl]-amide 152 6 2-(2-chloro-4-fluoro-phenyl)- N-[6-(2-amino-ethyl- 2 δ 8.05~7.85(m, 3H), 7.79(d, 1H), 7.61(d, 1H), 7-hydroxy-1H-benzoimidazole- amino)-pyridin-3-yl]- 7.42(t, 1H), 7.14(d, 1H), 6.94(d, 1H), 4-carboxylic acid[2-(5- methanesulfonamide 3.80~3.60(m, 4H), 2.92(t, 3H) methanesulfonylamino-pyridin- 2-ylamino)-ethyl]-amide 153 6 2-(2-chloro-4-fluoro-phenyl)- N-[6-(2-amino-ethyl- 2 δ 7.92(m, 1H), 7.89(d, 1H), 7.58(d, 2H), 7.45(m, 7-hydroxy-1H-benzoimidazole- amino)-pyridin-3-yl]- 3H), 7.29(m, 3H), 6.92(d, 1H), 6.78(d, 1H), 4-carboxylic acid{2-[5- p-toluenesulfonamide 3.72(t, 2H), 3.61(t, 2H), 2.37(s, 3H) (toluene-4-sulfonylamino)- pyridin-2-ylamino]ethyl}- amide 154 6 2-(2-chloro-4-fluoro-phenyl)- histamine 2 δ 8.79(s, 1H), 8.00~7.0 2H), 7.62(d, 1H), 7-hydroxy-1H-benzoimidazole- 7.50~7.35(m, 2H), 6.93(d, 1H), 3.76(t, 2H), 4-carboxylic acid[2-(1H- 3.76(t, 2H), 3.10(t, 2H) imidazol-4-yl)-ethyl]-amide 155 6 2-(2-chloro-4-fluoro-phenyl)- N-[6-(2-amino-ethyl- 2 δ 8.57(s, 1H), 8.10~7.95(m, 2H), 7.88(d, 1H), 7-hydroxy-1H-benzoimidazole- amino)-pyridin-3-yl]- 7.74(d, 1H), 7.50~7.30(m, 2H), 6.95(d, 1H), 4-carboxylic acid[2-(5- acetamide 4.10(t, 2H), 3.65(t, 2H), 2.13(s, 3H) acetylamino-pyridin-2-ylamino)- ethyl]-amide 156 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-Amino-ethyl)- 2 δ 7.97~7.80(m, 2H), 7.61(d, 1H), 7.59(d, 2H), 7-hydroxy-1H-benzoimidazole- phenyl]-2-(4-methyl- 7.40(t, 1H), 7.25(d, 2H), 6.92(d, 1H), 3.67(t, 2H), 4-carboxylic acid(2-{4-[2- piperazin-1-yl)-acetamide 3.34(s, 2H), 3.10~2.75(m, 13H) (4-methyl-piperazin-1-yl)- acetylamino]-phenyl}-ethyl)- amide 157 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.97~7.83(m, 2H), 7.61(d, 1H), 7.50(d, 2H), 7-hydroxy-1H-benzoimidazole- phenyl]-2-(4-ethyl- 7.39(t, 1H), 7.25(d, 2H), 6.91(d, 1H), 3.67(t, 2H), 4-carboxylic acid(2-{4-[2- piperazin-1-yl)-acetamide 3.34(s, 4H), 3.21(q, 2H), 3.05~2.75(m, 8H), (4-ethyl-piperazin-1-yl)-acetyl- 1.35(t, 3H) amino]-phenyl}-ethyl)amide 158 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.99(m, 1H), 7.84~7.70(m, 2H), 7.52(d, 2H), 7-hydroxy-1H-benzoimidazole- phenyl]-2-dimethyl- 7.35~7.25(m, 3H), 6.77(d, 1H), 4.08(s, 2H), 4-carboxylic acid{2-[4-(2- amino-acetamide 3.73(s, 2H), 2.97(m, 8H) dimethylamino-acetylamino)- phenyl]-ethyl}-amide 159 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.94~7.82(m, 2H), 7.60(d, 1H), 7.52(d, 2H), 7-hydroxy-1H-benzoimidazole- phenyl]-2-diethylamino- 7.40(t, 1H), 7.28(d, 2H), 6.89(d, 1H), 4.08(s, 4-carboxylic acid{2-[4-(2- acetamide 2H), 3.68(t, 2H), 3.31(q, 4H), 2.94(t, 2H), diethylmaino-acetylamino)- 1.34(t, 6H) phenyl]-ethyl}-amide 160 7 2-(3-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 (1H, d), 7.90(1H, m), 7.72(1H, d), 7.47(2H, d), 7-hydroxy-1H-benzoimidazole- phenyl]-p-toluene- 7.39(1H, m), 7.13–7.06(4H, m), 6.95(2H, d), 4-carboxylic acid{2-[4- sulfonamide 6.75(1H, d), 3.63(2H, t), 2.85(2H, t), 2.23(3H, s) (toluene-4-sulfonylamino)- phenyl]-ethyl}amide 161 7 2-(3-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 8.19(1H, d), 7.95(1H, m), 7.74(1H, d), 7-hydroxy-1H-benzoimidazole- phenyl]-methane- 7.42(1H, t), 7.24(2H, d), 7.13(2H, d), 6.75(1H, 4-carboxylic acid[2-(4- sulfonamide d), 3.68(2H, t), 2.91(2H, t), 2.81(3H, s) methanesulfonylamino-phenyl)- ethyl]-amide 162 1 7-hydroxy-2-phenyl-1H-benzo- n-butylamine 3 δ 7.95–7.70(2H, m), 7.69(1H, d), 7.60–7.42(1H, 309 imidazole-4-carboxylic acid m), 7.41–7.23(2H, m), 3.42(2H, t), butylamide 1.78–1.56(2H, m), 1.55–1.34(2H, t), 0.97(3H, t) 163 1 7-Hydroxy-2-phenyl-1H-benzo- 1,3-diaminopropane 3 δ 8.10(1H, d), 7.90(1H, d), 7.68(1H, d), 310 imidazole-4-carboxylic acid 3 7.67–7.53(3H, m), 6.81(1H, d), 3.65(2H, t), (3-amino-propyl)-amide 3.22–3.00(2H, t), 2.05(2H, t) 164 1 7-hydroxy-2-phenyl-1H-benzo- 1-(3-aminopropyl)-2- 3 δ 8.04(1H, d), 7.81(1H, d), 7.75–7.66(3H, m), 378 imidazole-4-carboxylic acid prolidinone 6.96(1H, d), 6.87(1H, d), 3.53–3.41(6H, m), [3-(2-oxo-prolidine-1-yl)- 2.39(2H, t), 2.03(2H, t), 1.90(2H, m) propyl]-amide 165 1 7-hydroxy-2-phenyl-1H-benzo- 1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.17(2H, d), 7.84(1H, d), 7.75(1H, 361 imidazole-4-carboxylic acid imidazole s), 7.72–7.62(3H, m), 7.55(1H, s), 6.88(1H, d), (3-imidazol-1-yl-propyl)- 4.40(2H, t), 3.57(2H, t), 2.28(2H, m) amide 166 1 7-hydroxy-2-phenyl-1H-benzo- 4-(3-aminopropyl)- 3 δ 8.10–8.11(2H, m), 7.86(2H, d), 380 imidazole-4-carboxylic acid morpholine 7.84–7.69(1H, m), 7.63–7.59(2H, m), 4.10(2H, (3-morpholine-4-yl-propyl)- t), 4.06(2H, t), 3.80(2H, t), 3.65(2H, t), amide 3.54(2H, t), 3.15(2H, t), 2.14(2H, m) 167 1 7-hydroxy-2-phenyl-1H-benzo- 3-(2-methyl-imidazol-1-yl)- 3 δ 8.18–8.11(2H, m), 7.84(1H, d), imidazole-4-carboxylic acid propylamine 7.73–7.63(4H, m), 7.40(1H, d), 6.89(1H, d), [3-(2-methyl-imidazol-1-yl)- 4.28(2H, t), 3.59(2H, t), 2.63(3H, s), 2.25(2H, m) propyl]-amide 168 2 2-(4-chloro-phenyl)-7-hydroxy- n-butylamine 3 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 6.92(1H, 343 1H-benzoimidazole-4-carboxylic d), 3.42(2H, t), 1.78–1.56(2H, m), acid butylamide 1.55–1.34(2H, t), 0.97(3H, t) 169 2 2-(4-chloro-phenyl)-7-hydroxy- 1-(3-aminopropyl)-2- 3 δ 8.21–8.11(2H, m), 7.82(1H, d), 7.63–7.53(2H, 412 1H-benzoimidazole-4-carboxylic pyrrolidone m), 6.86(1H, m), 3.60–3.38(6H, m), 2.38(2H, acid[3-(2-oxoprolidin-1-yl)- t), 2.03(2H, t), 1.89(2H, m) propyl]-amide 170 2 2-(4-chloro-phenyl)-7-hydroxy- 1-(3-aminopropyl)- 3 δ 9.03(1H, d), 8.18(2H, t), 7.81(1H, d), 7.74(1H, 395 1H-benzoimidazole-4-carboxylic imidazole d), 7.64–7.53(3H, m), 6.84(1H, d), 4.40(2H, t), acid(3-imidazole-1-yl-propyl)- 3.60(2H, t), 2.29(2H, m) amide 171 2 2-(4-chloro-phenyl)-7-hydroxy- 4-(3-aminopropyl)- 3 δ 8.21–8.10(2H, m), 7.85(1H, d), 414 1H-benzoimidazole-4-carboxylic morphorine 7.61–7.54(2H, m), 6.80(1H, d), 4.05(2H, t), acid(3-morphorine-4-yl-propyl)- 3.81(2H, t), 3.68–3.46(4H, m), 3.17(2H, t), amide 2.11(2H, m) 172 2 2-(4-chloro-phenyl)-7-hydroxy- 3-(2-phenyl-imidazol-1-yl)- 3 δ 8.13(2H, d), 7.87(1H, d), 7.70(1H, d), 473 1H-benzoimidazole-4-carboxylic propylamine 7.64–7.53(5H, m), 7.47–7.25(3H, m), 6.80(1H, acid[3-(2-pentyl-imidazol-1- d), 4.41(2H, t), 3.53(1H, t), 2.27(2H, m) yl)-propyl]-amide 173 2 2-(4-chloro-phenyl)-7-hydroxy- 3-(4-methyl-imidazole-1- 3 δ 8.85(1H, d), 8.17(2H, t), 7.87(1H, m), 409 1H-benzoimidazole-4-carboxylic yl)-propylamine 7.68–7.57(2H, m), 7.40(1H, d), 6.89(1H, d), acid[3-(4-methyl-imidazol-1- 4.32(2H, t), 3.59(2H, m), 2.37–2.20(5H, m) yl)-propyl]-amide 174 2 2-(4-chloro-phenyl)-7-hydroxy- 3-(4,5-dichloro-imidazole- 3 δ 8.13(2H, t), 7.85–7.78(2H, m), 7.65–7.55(2H, 474 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine m), 6.87(1H, d), 4.18(2H, t), 3.54(2H, m), acid[3-(4,5-dichloro-imidazol- 2.18(2H, m) 1-yl)-propyl]-amide 175 2 2-(4-chloro-phenyl)-7-hydroxy- 3-(2-methyl-imidazole- 3 δ 8.21–8.09(3H, m), 7.68(1H, d), 421 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.60–7.55(3H, m), 7.36(1H, d), 4.28(2H, t), acid[3-(2-methyl-imidazol-1- 3.63(2H, m), 2.60(3H, s), 2.28(2H, m) yl)-propyl]-amide 176 3 2-(2,4-dichloro-phenyl)-7- n-butylaine 3 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 377 hydroxy-1H-benzoimidazole-4- 7.37–7.23(4H, m), 6.92(1H, d), 3.42(2H, t), carboxylic acid butylamide 1.78–1.56(2H, m), 1.55–1.34(2H, t), 0.97(3H, t) 177 3 2-(2,4-dichloro-phenyl)-7- 1-(3-aminopropyl)-2- 3 δ 8.07–7.74(3H, m), 7.73–7.49(1H, m), 6.90(1H, 446 hydroxy-1H-benzoimidazole-4- pyrolidione d), 3.60–3.38(6H, m), 2.38(2H, t), 2.03(2H, t), carboxylic acid[3-(2-oxo- 1.89(2H, m) pyrolidin-1-yl)-propyl]-amide 178 3 2-(2,4-dichloro-phenyl)-7- 1-(3-aminopropyl)- 3 δ 9.02(1H, s), 7.90–7.72(4H, m), 7.64–7.46(2H, 429 hydroxy-1H-benzoimidazole-4- imidazole m), 6.88(1H, d), 4.37(2H, t), 3.53(2H, t), carboxylic acid(3-imidazol-1- 2.26(2H, m) yl-propyl)-amide 179 3 2-(2,4-dichloro-phenyl)-7- 4-(3-aminopropyl)- 3 δ 8.03–7.76(3H, m), 7.75–7.45(1H, m), 6.85(1H, 448 hydroxy-1H-benzoimidazole-4- morphorine d), 4.05(2H, t), 3.81(2H, t), 3.68–3.46(4H, m), carboxylic acid(3-morphorin- 3.17(2H, t), 2.11(2H, m) 4-yl-propyl)-amide 180 3 2-(2,4-dichloro-phenyl)-7- 3-(2-phenyl-imidazol-1- 3 δ 8.15(d, 2H), 8.11(s, 1H), 7.86(s, 1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine 7.64~7.29(m, 5H), 7.29~7.25(m, 3H), 6.56(d, carboxylic acid[3-(2-phenyl- 1H), 4.41(t, 2H), 3.53(t, 2H), 2.27(q, 3H) imidazol-1-yl)-propyl]-amide 181 3 2-(2,4-dichloro-phenyl)-7- 3-(4-methyl-imidazol-1- 3 δ 8.84(s, 1H), 7.91~7.73(m, 3H), 7.58(m, 1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine 7.38(s, 1H), 6.85(d, 1H), 4.29(t, 2H), 3.54(t, 2H), carboxylic acid[3-(4-methyl- 2.34~2.25(m, 5H) imidazol-1-yl)-propyl]-amide 182 3 2-(2,4-dichloro-phenyl)-7- 3-(4,5-dichloro-imidazol-1- 3 δ 7.91~7.81(m, 4H), 7.52(s, 1H), 6.96(d, 1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine 4.15(t, 2H), 3.64(t, 2H), 2.13(q, 2H) carboxylic acid[3-(4,5-dichloro- imidazol-1-yl)-propyl]-amide 183 3 2-(2,4-dichloro-phenyl)-7- 3-(2-methyl-imidazol-1- 3 δ 8.11~8.09(m, 3H), 7.61(m, 2H), 7.45(s, 1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine 6.88(d, 1H), 4.31(t, 2H), 3.46(t, 2H), 2.25(q, carboxylic acid[3-(2-methyl- 2H), 2.33(s, 3H) imidazol-1-yl)-propyl]-amide 184 3 2-(2,4-dichloro-phenyl)-7- 3-(2-isopropyl-imidazol- 3 δ 8.10~8.05(m, 3H), 7.58(m, 2H), 7.40(s, 1H), hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 6.88(d, 1H), 4.22(t, 2H), 3.60(t, 2H), 3.02(m, carboxylic acid[3-(2- 1H), 1.3(s, 6H) isopropyl-imidazol-1-yl)- propyl]-amide 185 4 2-(4-fluoro-phenyl)-7-hydroxy- 1-(3-aminopropyl)- 3 δ 8.89(1H, s), 8.21(2H, m), 7.83(1H, d), 1H-benzoimidazole-4-carboxylic imidazole 7.49(1H, s), 7.38–7.24(3H, m), 6.90(1H, d), acid(3-imidazol-1-yl-propyl)- 4.31(2H, t), 3.56(2H, t), 2.38–2.33(2H, m) amide 186 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(2-isopropyl-imidazol- 3 δ 8.26–8.21(2H, m), 7.84(1H, d), 7.65(1H, 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine s), 7.46–7.37(3H, m), 6.88(1H, d), 4.34(2H, t), acid[3-(2-isopropyl-imidazol- 3.62(2H, t), 3.52–3.43(1H, m), 2.27(2H, m), 1-yl)-propyl]-amide 1.36(6H, d) 187 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(4-methyl-imidazole- 3 δ 8.89(1H, s), 8.21(2H, m), 7.83(1H, d), 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.43(3H, m), 6.90(1H, d), 4.31(2H, t), 3.56(2H, acid[3-(4-methyl-imidazol-1- t), 2.38–2.27(5H, m) yl)-propyl]-amide 188 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(2-methyl-imidazol- 3 δ 8.29(2H, m), 7.78(1H, d), 7.49(1H, s), 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.35–7.24(3H, m), 6.70(1H, d), 4.26(2H, t), acid[3-(2-methyl-imidazol-1- 3.64(2H, t), 2.95(3H, s), 2.28(2H, m) yl)-propyl]-amide 189 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(2-ethyl-imidazol- 3 δ 8.27(2H, m), 7.79(1H, d), 7.51(1H, s), 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.33–7.25(3H, m), 6.72(1H, d), 4.27(2H, t), acid[3-(2-ethyl-imidazol-1- 3.65(2H, t), 2.90(2H, q), 2.28(2H, m), 1.25(3H, t) yl)-propyl]-amide 190 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(4,5-dichloro-imidazol-1- 3 δ 8.24–8.16(2H, m), 8.04(1H, d), 7.79(1H, d), 1H-benzoimidazole-4-carboxylic yl)-propylamine 7.45–7.33(2H, m), 6.99–6.84(1H, m), 4.18(2H, acid[3-(4,5-dichloro-imidazol- t), 3.54(2H, t), 2.18(2H, m) 1-yl)-propyl]-amide 191 5 2-(2,4-difluoro-phenyl)-7- 3-(2-isopropyl-imidazol- 3 δ 8.20(1H, q), 8.18–7.97(1H, m), 7.86(1H, d), hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 7.64(1H, s), 7.45(1H, s), 7.39–7.24(1H, m), carboxylic acid[3-(2-isopropyl)- 6.86(1H, d), 4.33(2H, t), 3.60(2H, t), 3.49(1H, imidazol-1-yl)-propyl]-amide m), 2.26(2H, t), 1.36(3H, s), 1.34(3H, s) 192 5 2-(2,4-difluoro-phenyl)-7- 1-(3-aminopropyl)- 3 δ 8.23(1H, q), 7.13–7.97(1H, m), 7.84(1H, d), hydroxy-1H-benzoimidazole-4- imidazole 7.74(1H, s), 7.56(1H, s), 7.31–7.24(2H, m), carboxylic acid(3-imidazol-1- 6.84(1H, d), 4.40(2H, t), 3.56(2H, t), 2.28(2H, t) yl-propyl)-amide 193 5 2-(2,4-difluoro-phenyl)-7- 3-(4-methyl-imidazol- 3 δ 8.22(1H, q), 8.14–7.98(1H, m), 7.84(1H, d), hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 7.40–7.27(3H, m), 6.85(1H, d), 4.30(2H, t), carboxylic acid[3-(4-methyl- 3.57(2H, t), 2.30(5H, m) imidazol-1-yl)-propyl]-amide 194 5 2-(2,4-difluoro-phenyl)-7- 3-(4,5-dichloro-imidazol- 3 δ 8.19–8.03(2H, m), 7.81(2H, m), hydroxy-1H-benzoimidazole-4- 1-yl)propylamine 7.39–7.29(1H, m), 6.85(1H, d), 4.17(2H, t), carboxylic acid[3-(4,5-dichloro- 3.52(2H, t), 2.16(2H, t) imidazol-1-yl)-propyl]-amide 195 5 2-(2,4-difluoro-phenyl)-7- 3-(2-methyl-imidazol- 3 δ 8.21(1H, q), 8.06(1H, m), 7.85(1H, d), hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 7.62(1H, s), 7.39–7.27(2H, m), 6.87(1H, d), carboxylic acid[3-(2-methyl- 4.30(2H, t), 3.58(2H, t), 2.63(3H, s), 2.25(2H, t) imidazol-1-yl)-propyl]-amide 196 5 2-(2,4-difluoro-phenyl)-7- 3-(2-ethyl-imidazol-1- 3 δ 8.29–8.05(2H, m), 7.86(1H, d), 7.64(1H, s), hydroxy-1H-benzoimidazole-4- yl)-propylamine 7.43(1H, s), 7.38–7.31(1H, m), 6.95(1H, d), carboxylic acid[3-(2-ethyl- 4.29(2H, t), 3.57(2H, t), 3.03(2H, q), 2.25(2H, t), imidazol-1-yl)-propyl]-amide 1.34(3H, t) 197 5 2-(2,4-difluoro-phenyl)-7- 3-(4,5-dichloro-imidazol-1- 3 8.19–8.03(2H, m), 7.81(2H, m), hydroxy-1H-benzoimidazole-4- yl)-propylamine 7.39–7.29(1H, m), 6.85(1H, d), 4.17(2H, t), carboxylic acid[3-(4,5-dichloro- 3.52(2H, t), 2.16(2H, t) imidazol-1-yl)-propyl]-amide 198 6 2-(2-chloro-4-fluoro-phenyl)- 1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.00–7.88(2H, m), 7.74(1H, s), 7-hydroxy-1H-benzoimidazol-4- imidazole 7.66–7.57(2H, m), 7.46–7.41(1H, m), 6.95(1H, carboxylic acid(3-imidazol-1- d), 4.38(2H, t), 3.52(2H, t), 2.25(2H, t) yl-propyl)-amide 199 6 2-(2-chloro-4-fluoro-phenyl)- 3-(4-methyl-imidazol-1- 3 δ 8.88(1H, s), 8.00–7.87(2H, m), 7.60(1H, m), 7-hydroxy-1H-benzoimidazol-4- yl)-propylamine 7.41(2H, m), 6.94(1H, d), 4.28(2H, t), 3.54(2H, carboxylic acid[3-(4-methyl- t), 2.29(3H, s), 2.22(2H, t) imidazol-1-yl)-propyl]-amide 200 6 2-(2-chloro-4-fluoro-phenyl)- 3-(4,5-dichloro-imidazol- 3 δ 7.94(1H, m), 7.85(1H, m), 7.76(1H, s), 7-hydroxy-1H-benzoimidazol-4- 1-yl)-propylamine 7.48(1H, d), 7.30(1H, t), 6.76(1H, d), 4.17(2H, t), carboxylic acid[3-(4,5-dichloro- 3.56(2H, t), 2.16(2H, t) i midazol-1-yl)-propyl]-amide 201 6 2-(2-chloro-4-fluoro-phenyl)- 3-(2-methyl-imidazol- 3 δ 7.83(1H, m), 7.50(1H, m), 7.39(1H, s), 7-hydroxy-1H-benzoimidazol-4- 1-yl)-propylamine 7.23(2H, m), 7.13(1H, s), 6.76(1H, d), 4.20(2H, carboxylic acid[3-(2-methyl- t), 3.57(2H, t), 2.47(3H, s), 2.03(2H, t) imidazol-1-yl)-propyl]-amide 202 7 2-(3-chloro-4-fluoro-phenyl)- 3-(4-methyl-imidazol-1- 3 δ 8.87(1H, s), 8.37(1H, d), 8.17(1H, m), 7-hydroxy-1H-benzoimidazol-4- yl)-propylamine 7.83(1H, d), 7.59(1H, t), 7.40(1H, s), 6.84(1H, carboxylic acid[3-(4-methyl- d), 4.33(2H, t), 3.60(2H, t), 2.25(5H, m) imidazol-1-yl)-propyl]-amide 203 7 2-(3-chloro-4-fluoro-phenyl)- 1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.37(1H, d), 8.17(1H, m), 7-hydroxy-1H-benzoimidazol-4- imidazol 7.83(1H, m), 7.75(1H, s), 7.61–7.43(2H, m), carboxylic acid(3-imidazol-1- 6.82(1H, d), 4.41(2H, t), 3.60(2H, t), 2.30(2H, t) yl-propyl)-amide

EXAMPLE 204 Preparation of 7-hydroxy-2-[4-(2-morpholin-4-yl-ethylamino)-phenyl]-1H-benzoimidazole-4-carboxylic acid [3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide (1) Preparation of 3-[(4-nitro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluenesulfonic acid (6.30 g, 33.1 mmol) was added to 50 ml of benzene and the resulting mixture was refluxed while removing water using a dean-stock trap. Added thereto were 3-amino-4-methoxy benzoic acid methyl ester (3 g, 16.6 mmol) obtained in step 1 of Preparation Example 1 and 4-nitrobenzonitrile (2.94 g, 19.9 mol), followed by stirring at 160° C. for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding NaHCO₃ thereto, extracted with ethyl acetate, the extract was dried over MgSO₄ and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.83 g, 8.59 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.12–8.09 (m, 2H), 7.82 (d,1H), 7.70–7.69 (m, 1H), 6.98 (d, 1H), 4.91 (bs, 2H), 3.89(s, 6H)

(2) Preparation of 2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

3-[(4-nitro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (1.63 g, 4.95 mmol) was dissolved in 50% methanol, and 5% NaOCl was added dropwise thereto at room temperature. After checking the reaction by TLC, Na₂CO₃ (1.05 g, 9.38 mmol) seas added dropwise thereto and refluxed for 40 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (0.75 g, 2.28 mmol) in a yield of 46%.

¹H NMR (CDCl₃): δ 10.90 (bs, 1H), 8.36–8.31 (m, 4H), 7.95 (d, 1H), 6.78 (d, 1H), 4.16 (s, 3H), 4.01 (s, 3H)

(3) Preparation of 2-(4-amino-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (0.63 g, 1.92 mmol) obtained in step 2 was dissolved in 15 ml of EtOH, 0.1 g of 10% Pd/C was added thereto and stirred for 24 hours while hydrogen was supplied thereto from a balloon fulfilled with H₂ gas. The resulting solution was filtered and dried to obtain the title compound (0.57 g, 1.92 mmol) in a yield of 100%.

¹H NMR (CH₃OH-d₄): δ 10.48 (bs, 1H), 7.93 (d, 2H), 7.82 (d, 1H), 6.77 (d, 2H), 6.71 (d, 1H), 4.11 (s,3H), 3.98 (s, 3H)

(4) Preparation of 2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester

2-(4-amino-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (160 mg, 0.54 mmol) obtained in step 3 was dissolved in DMF, cesium carbonate (0.53 g, 1.61 mmol) was added thereto and stirred for 5 min. Added thereto were 2-chloroethylmorpholine (0.12 g, 0.64 mmol) and potassium iodide (0.18 g, 1.08 mmol), followed by stirring for 24 hours. Then, the resulting solution was extracted with ethyl acetate, the extract was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (91 mg, 0.22 mmol) in a yield of 41%.

¹H NMR (CH₃OH-d₄): δ 7.97 (d, 1H), 7.57 (d, 2H), 6.77–6.73 (m, 3H), 4.54 (t, 2H), 4.11 (s, 3H), 3.99 (s, 3H), 3.57–3.55(m, 4H), 2.64 (t, 2H), 2.31–2.28 (m, 4H)

(5) Preparation of 2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide

2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (22 mg, 0.05 mmol) was dissolved in THF/H₂O, LiOHH₂O (6.7 mg, 0.16 mmol) was added thereto and stirred at room temperature. The resulting solution was filtered to remove residual LiOHH₂O, and the solvent was removed. The residue was dried and dissolved in DMF. Added thereto were 4,5-dichloro-1-(3-aminopropyl)imidazole (12.5 mg, 0.06 mmol), EDCI (30.9 mg, 0.16 mmol), DMAP (65.6 mg, 0.54 mmol) and HOBt (21.8 mg, 0.16 mmol), followed by stirring at room temperature. The resulting solution was extracted with ethyl acetate and concentrated under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (19 mg, 0.03 mmol) in a yield of 63%.

¹H NMR (CH₃OH-d₄): δ 7.93 (d, 1H), 7.77–7.75 (m, 3H), 7.52 (d, 2H), 6.92 (d, 1H), 4.17 (t, 2H), 4.06–4.02 (m, 5H), 3.58–3.56 (m, 4H), 3.50 (t, 2H), 2.66 (t, 2H), 2.31–2.29 (m, 4H), 2.16 (q, 2H)

(6) Preparation of 2-[(2-morpholinoethyl)-4-amino-phenyl]-7-hydroxy-1H-benzoimidazole-4-carboxylic acid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide

2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide (15 mg, 0.03 mmol) obtained in step 5 was dissolved in MC, BBr₃ (1.0M solution in MC, 0.3 mL, 0.3 mmol) was added thereto and stirred at room temperature for 48 hours. The reaction was stopped by adding water thereto and the resulting solution was extracted with MC/MeOH (7:1). The extract was concentrated under a reduced pressure and purified by silica gel chromatography to obtain the title compound (5.9 mg, 0.01 mmol) in a yield of 40%.

¹H NMR (CH₃OH-d₄): δ 7.95 (d, 1H), 7.81–7.79 (m, 4H), 7.55 (d, 1H), 6.94 (d, 1H), 4.15 (t, 2H), 3.94 (t, 2H), 3.59 (t, 2H), 3.58–3.56 (m, 4H), 2.64 (t, 2H), 2.32–2.30 (m, 4H), 2.18 (q, 2H)

TEST EXAMPLE 1

Assay for GSK-3β inhibiting activity

The GSK-3β inhibiting activity was determined in accordance with the method of Shultz et al. described in U.S. Pat. No. 6,153,618, with minor modifications by using phospho-CREB peptide as a substrate.

First, PCR (polymerase chain reaction) was carried out using human DNA as a template as well as primers which were designed to correspond to the 3′- and 5′ ends of the polynucleotide coding human GSK-3β gene (Genbank Accession No.: L33801). The BamH1/XhoI fragment of the amplified PCR product thus obtained was inserted into the pGex vector between the BamH1 and XhoI sites, and the vector obtained was transformed into E. coli BL21(DE3). The transformed cells thus obtained was incubated in LB agar plates (1% Bacto-trypton, 0.5% yeast extract, 1% NaCl) containing ampicillin (100 μl/ml) until the optical density at 600 nm reached about 0.5. The cultured mixture was cooled to 18° C. and isopropyl β-D-thiogalacto-pyranoside (IPTG) was added thereto to a final concentration of 0.5 mM. After 16 hours, the resultant was centrifuged at 10,000×g for 10 min, the collected cells were suspended in a buffer solution (30 mM Tris-HCl (pH 7.5), 100 mM NaCl, 5% glycerol, 2 mM DTT) and the cells were disrupted using Sonic Dismembrator (Fisher, U.S.A.) in a ice bath. The resulting solution was centrifuged at 16,000 rpm for 30 minutes. The supernatant was connected to GST (Glutathione-S-transferase) column (Pharmacia Biotech, U.S.A.) equilibrated in the same buffer solution, purified by glutathione affinity chromatography (eluent: 5 mM glutathione), and then, digested with thrombin to cleave the connecting site between the GST moiety and GSK-3β protein. The purified GSK-3β protein was diluted in a buffer solution (20 mM HEPES (pH 7.5), 5% glycerol, 2 mM DTT) to a final concentration of 50 mM NaCl and the resulting solution was subjected to mono S column chromatography (eluent: linear gradient from 0M to 1M NaCl buffer) using mono S column (Pharmacia Biotech, U.S.A.) equilibrated in the same buffer solution to obtain GSK-3β protein.

100 nM GSK-3β protein, 12.5 mM each of the compounds prepared in Examples 1 to 204 dissolved in DMSO, an assay buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 1 mM DTT), 100 μM phospho-CREB peptide (NEB, USA), 100 μM ATP, ³²P-ATP and 1 μCi were reacted at 30° C. for 1 hour. The reaction was stopped by adding 5 μl of 5% phosphoric acid to 25 μl of the resulting solution. The resulting mixture was centrifuged at 15,000 rpm for 10 min, 20 μl of the supernatant was added dropwise to Whatman p81 filter paper, and then, the resulting filter paper was washed with 0.5% phosphate buffer for 10 min. The filter paper was further washed 3 times and the enzymatic activity was determined by examining the extent of phospho-CREB peptide phosphorylation which is represented by the unit of count per minute (CPM), measured with a β-counter (Packard, USA).

The GSK-3β inhibiting activity was then calculated in accordance with the following equation:

$\text{Degree~~of~~Inhibition(\%)} = {100 \times \left\lbrack {1 - \frac{\text{CPM(sample)} - \text{CPM(blank)}}{\text{CPM(control)} - \text{CPM(blank)}}} \right\rbrack}$ wherein the blank represents a value obtained without the use of the enzyme and the compound of the present invention, and the control, in the absence of the compound of the present invention.

The IC₅₀ value of the inventive compound was determined from the degree of inhibition (%) and the result is shown in Table 3.

TABLE 3 Ex- IC₅₀ IC₅₀ IC₅₀ IC₅₀ am. (μM) Exam. (μM) Exam. (μM) Exam. (μM) 1 >1 52 >1 103 >5 154 >1 2 >1 53 >1 104 >1 155 >1 3 >1 54 >1 105 0.05 156 0.28 4 >1 55 >1 106 0.015 157 0.49 5 0.3 56 0.7 107 0.05 158 0.23 6 >1 57 0.58 108 >1 159 0.68 7 >1 58 0.67 109 0.03 160 >1 8 >1 59 0.16 110 0.28 161 0.09 9 0.18 60 0.35 111 >1 162 0.24 10 0.04 61 >1 112 0.04 163 >1 11 >5 62 >1 113 0.19 164 0.84 12 0.2 63 0.45 114 0.001 165 0.08 13 0.36 64 0.03 115 0.026 166 >1 14 >1 65 0.06 116 0.003 167 0.1 15 0.11 66 >1 117 0.03 168 >1 16 0.7 67 0.16 118 >5 169 >1 17 0.24 68 0.017 119 >5 170 0.19 18 >1 69 >1 120 0.07 171 >1 19 >1 70 >1 121 0.03 172 0.8 20 4.1 71 >1 122 0.2 173 0.1 21 >5 72 0.12 123 0.05 174 0.04 22 >1 73 >1 124 0.07 175 0.28 23 0.68 74 >1 125 >1 176 0.45 24 >5 75 0.009 126 >1 177 0.2 25 >1 76 0.05 127 0.18 178 0.04 26 >1 77 0.033 128 0.15 179 >1 27 >1 78 >1 129 0.12 180 0.21 28 0.74 79 0.12 130 0.33 181 0.03 29 0.08 80 0.07 131 0.17 182 0.008 30 >1 81 >1 132 0.19 183 0.06 31 >1 82 >1 133 >1 184 0.15 32 0.5 83 >1 134 0.04 185 >1 33 >1 84 >1 135 >1 186 0.05 34 >1 85 >5 136 0.24 187 0.01 35 0.007 86 0.25 137 0.005 188 0.002 36 >1 87 0.23 138 >1 189 >1 37 >1 88 0.22 139 0.12 190 0.006 38 >1 89 0.32 140 >1 191 0.09 39 >1 90 0.13 141 0.043 192 0.008 40 >1 91 >1 142 0.001 193 0.02 41 >1 92 0.08 143 0.002 194 0.004 42 >1 93 >1 144 0.006 195 0.03 43 >1 94 >5 145 0.002 196 0.02 44 >1 95 >1 146 0.07 197 0.003 45 0.02 96 0.022 147 0.21 198 0.02 46 >5 97 0.17 148 >1 199 0.01 47 >5 98 >1 149 0.14 200 0.002 48 >5 99 1 150 0.06 201 0.07 49 0.6 100 0.2 151 0.4 202 0.009 50 0.6 101 >1 152 0.24 203 0.003 51 0.87 102 0.23 153 0.05 204 >5

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims. 

1. A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof:

wherein: n is 0, 1, 2 or 3; R¹, R² and R³ are each independently hydrogen, hydroxy, halogen or morpholin-1-yl-ethylamino; R⁴ is hydrogen; and R⁵ is linear or cyclic C₁–C₆ alkyl optionally having one or more substituents, the carbon of the alkyl being optionally replaced with nitrogen, sulfur or oxygen, wherein the substituent is: hydroxy; halogen; allyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido; alkanesulfonyl; amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amido, dioxoisoindole and sulfonylamino; an aromatic group having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido, the aromatic ring having nitrogen, sulfur or oxygen; or cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido; an aromatic group optionally having one or more substituents, the aromatic ring having optional nitrogen, sulfur or oxygen, wherein the substituent is; hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; or linear or cyclic C₁–C₆ alkyl optionally having one or more substituents, the alkyl having an optional nitrogen, sulfur or oxygen linkage and the substituent of the alkyl being: hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro; amido; dioxoisoindole; and a sulfonylamino having an aromatic group substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, sulfonylamido, alkanesulfonyl or amido; an aromatic group optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, sulfonylamide, alkanesulfonyl and amido, the aromatic ring containing nitrogen, sulfur or oxygen; or a cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido; or R⁴ and R⁵ form, together with the —N—(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycle optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, the heterocycle containing optional nitrogen or oxygen.
 2. The compound of claim 1, wherein R⁵ is C¹–C⁴ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, and an aromatic group, the aromatic group optionally having one or more substituents selected from the group consisting of OH, C¹–C⁴ alkyloxy, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino and dioxoisoindole; cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂; C₁–C₄ alkyl carrying a morpholine or oxopyrrolidine group which is optionally substituted with OH, NH₂, NO₂ or —O—; C₁–C₄ alkyl or C₁–C₄ aminoalkyl carrying a pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, isothiazole, thiazolidine, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,2,5-thiadiazole, 1,2,3-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine or triazine group which is optionally having one or more substituents selected from the group consisting of Cl, OH, NH₂, NO₂, C₁–C₄ and phenyl; cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂; an aromatic group optionally having one or more substituents selected from the group consisting of OH; NH₂; hydroxyalkyl; aminoalkyl; NO₂; and a C₁–C₄ alkyl group optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino, dioxoisoindole and thiophensulfonylamino; or R⁴ R⁵ form, together with the —N—(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycle optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂, the heterocycle containing 1 to 3 nitrogen, sulfur or oxygen atom.
 3. The compound of claim 1, wherein R⁵ is C₁–C₄ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂, NO₂, morpholine, nitropyridineamino, pyridine, oxopyrrolidin, imidazole optionally having a Cl, CH₃ or phenyl substituent; and phenyl optionally having one or more substituents selected from the group consisting of OH, NH₂, methoxy, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino and dioxoisoindole; cyclic C₃–C₈ alkyl optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂; phenyl optionally having one or more substituents selected from the group consisting of OH; NH₂; NO₂; and C₁–C₄ alkyl optionally having a OH, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino, tolunesulfonylamino, dioxoisoindole or thiophensulfonylamino substituent; or R⁴ and R⁵ form, together with —N—(CH₂)_(n)— moiety to which they are attached, a piperidine ring optionally having one or more substituents selected from the group consisting of OH, NH₂ and NO₂.
 4. A process for preparing the compound of formula (IA) which comprises reacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol to obtain compound (III); adding anhydrous p-toluenesulfonic acid and benzonitrile to the compound (III) thus obtained, refluxing the mixture at 80 to 200° C., adding NaOCl thereto at room temperature and purifying by silica gel column chromatography to obtain compound (IV); dissolving the compound (IV) thus obtained in an alcohol, adding an aqueous alkali solution thereto and refluxing the mixture to obtain compound (V); dissolving the compound (V) thus obtained in an organic solvent, adding a Lewis acid thereto and refluxing the mixture to obtain compound (VI); dissolving the compound (V) thus obtained in alcohol, adding a strong acid thereto at room temperature and refluxing the mixture to obtain compound (VII); dissolving the compound (VII) thus obtained and (4-bromomethylphenoxy)-methyl polystyrene Wang resin in an organic solvent, adding a base and K1 thereto and stirring the mixture at 50 to 60° C. for 1 to 24 hours to obtain compound (VIII); dissolving the compound (VIII) thus obtained in an organic solvent, adding an alcohol solution of an alkali hydroxide thereto and refluxing the mixture to obtain compound (IX); dissolving the compound (IX) thus obtained in an organic solvent, adding R⁴N(CH₂),R⁵ and a coupling agent thereto and stirring the mixture at room temperature to obtain compound (X); and dissolving the compound (X) thus obtained in CH₂Cl₂, adding trifluoroacetic acid thereto and stirring the mixture at room temperature to obtain compound (Ia):

wherein, n, R¹, R², R³, R⁴ and R⁵ have the same meanings as defined in claim
 1. 5. A process for preparing the compound of formula (Ib) which comprises reacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol to obtain compound (III); adding p-toluenesulfonic acid, benzene and 4-nitrobenzonitrile thereto, refluxing the mixture at 80 to 200° C., adding NaOCl thereto at room temperature and purifying by silica gel column chromatography to obtain compound (XI); dissolving the compound (XI) thus obtained in an organic solvent, adding an aqueous alkali solution thereto, refluxing the mixture and purifying by silica gel column chromatography to obtain compound (XII); dissolving the compound (XII) thus obtained in an alcohol, adding Pd/C thereto and refluxing the mixture to obtain compound (XIII); dissolving the compound (XIII) thus obtained in an organic solvent, adding a base, 2-chloroethylmorphine and potassium iodide thereto and stirring the mixture at room temperature to obtain compound (XIV); dissolving the compound (XIV) obtained thus in an organic solvent, adding an alkali hydrate, stirring the mixture at room temperature to obtain compound (XV); dissolving the compound (XV) thus obtained in an organic solvent, adding 4,5-dichloro-1-(3-aminoprophyl) imidazole and a coupling agent, stirring the mixture at room temperature and purifying by silica gel column chromatography to obtain compound (XVI); and dissolving the compound (XVI) thus obtained in MC, adding a Lewis acid thereto, stirring the mixture, concentrating the resulting solution under a reduced pressure and purifying by silica gel column chromatography to obtain compound (Ib)


6. A pharmaceutical composition for inhibiting GSK-3β comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 